WO2024224066A1 - Neurodegenerative disorders - Google Patents

Abstract

The invention relates to a peptide derivative of Formula (I). The peptide derivative may be used in treating, ameliorating or preventing a neurodegenerative disorder, such as Alzheimer's disease; Parkinson's disease; Huntington's disease; motor neurone disease; Spinocerebellar ataxia (SCA) type 1, type 2, and type 3; Amyotrophic Lateral Sclerosis (ALS); schizophrenia; Lewy-body dementia; and Frontotemporal Dementia.

Description

Neurodegenerative Disorders The invention relates to neurodegenerative disorders, and in particular to novel peptide derivatives, compositions, therapies and methods for treating such conditions, for example Alzheimer's disease. Alzheimer's disease primarily affects men and women over the age of 65 and the likelihood of being diagnosed with the disease increases substantially with age. With the percentage of adults over the age of 65 expected to grow worldwide over the next 40 years, the incidence of Alzheimer's disease is expected to more than double, escalating from 21 million cases in 2010 to 53 million in 2050 (statistics from www.alzheimersresearchuk.org and www.alz.org). This exponential increase in the expected number of patients presenting with Alzheimer's disease not only represents a major area of unmet medical need, but offers a significant market opportunity for therapeutics and diagnostics as there is currently no fully effective method of treating the disease. The basic underlying brain mechanism for the cause of Alzheimer's disease has not yet been identified that could consequently be targeted pharmaceutically. The main contender for accounting for the process of neurodegeneration is the ‘amyloid hypothesis’, where neuronal death is attributed to disruption of the cell membrane by toxic deposits of amyloid, characteristic of post-mortem Alzheimer brain, and resulting from abnormal cleavage of amyloid precursor protein. However, this ‘amyloid hypothesis’ does not explain the co-pathology frequently observed with Alzheimer's and Parkinson's diseases, nor the characteristic selectivity of cells vulnerable to degeneration despite the potential ubiquity of amyloid in all brain cells, nor the absence of amyloid deposits in animal models of dementia, nor indeed the occurrence of amyloid in certain brain regions where cognitive deficits are not apparent. One clue for identifying the primary mechanism of neurodegeneration, could be that only various neuronal groups are primarily vulnerable. Moreover, the diverse cell sub- groups prone to Alzheimer's, Parkinson's and Motor Neurone Diseases nonetheless are adjacent to each other and form a continuous ‘hub’ extending from brainstem to forebrain that all send diffuse projections upwards and outwards to higher cerebral centres. Hence, despite their heterogeneity in transmitters, these neuronal groups have been collectively dubbed 'Global' neurons to distinguish them from the more familiar and localised circuits of cells in most other parts of the brain, such as cerebellum, thalamus, cortex etc. These selectively vulnerable Global neurons were previously identified, albeit using a different terminology (‘isodendritic core’) as pivotal in neurodegeneration several decades ago. The sub-groups of Global neurons have a specific feature in common that might explain the puzzling and as yet unanswered question as to why only these cells succumb to progressive death whilst their counterparts elsewhere in the brain, even when damaged by stroke, do not: they retain a robust plasticity into and throughout adulthood, accompanied by a specific sensitivity to substances aiding and sustaining growth - 'trophic factors'. In the developing brain, trophic factors work by stimulating calcium influx, which triggers a cascade of events within the cell, eventually resulting in selective differentiation and growth. However, in higher doses or with longer exposures, sustained calcium entry can be toxic to neurons. Most significantly, a further determining factor in whether or not calcium entry triggers trophic or toxic effects, is age: as neurons mature, an erstwhile trophic level of intracellular calcium becomes lethal. The inventors have previously proposed that the neurodegenerative process is in fact an aberrantly activated process of development. In support of this hypothesis, a hyper- trophy of the brainstem ‘hub’ neurons has actually been reported in Alzheimer brains (Bowser et al., 1997, Brain Pathol.7:723-30). If large areas of this hub are damaged, then more than one neurodegenerative disease will present, as occurs in the frequently seen but never as yet explained cases of co-pathology with Alzheimer's and Parkinson's diseases. Interestingly, all the neurons within the vulnerable hub of Global neurons, despite transmitter heterogeneity, all contain the familiar enzyme acetylcholinesterase (AChE). AChE is therefore present in neurons where it would be unable to perform its normal function, since such sub-groups of cells as the noradrenergic locus coeruleus, the dopaminergic substantia nigra, or the serotonergic raphe nuclei, in no cases contain the usual substrate, acetylcholine. A further unexpected deviation from its normal, enzymatic role is that the AChE is actually released from Global neurons, presumably as some kind of inter-cellular messenger in its own right. In general, AChE is now widely and well-established as a signalling molecule that has trophic activity in a diverse variety of situations in both neural and non-neural tissue. The inventors have previously shown that AChE, operating as a trophic agent independent of its enzymatic action, does indeed trigger calcium entry into neurons. It is possible therefore that within Global neurons, AChE has a dual non-classical action that ranges along a trophic-toxic axis, depending on amount, duration of availability and, most significantly, age. If standard neurons are damaged in adulthood, as in a stroke, others will compensate functionally. In contrast, Global neurons will respond by calling on their trophic resources in an attempt to regenerate. But because the subsequent calcium influx will be lethal in the older, mature cells, the resulting damage will trigger further attempts to compensate in a pernicious cycle that characterises neurodegeneration. Acetylcholinesterase (AChE) is expressed at different stages of development in various forms, all of which have identical enzymatic activity, but which have very different molecular composition. The ‘tailed’ (T-AChE) is expressed at synapses and the inventors have previously identified two peptides that could be cleaved from the C- terminus, one referred to as “T14”, within the other which is known as “T30”, and which both have strong sequence homology to the comparable region of β-amyloid. The AChE C-terminal peptide “T14”’ has been identified as being the salient part of the AChE molecule responsible for its range of non-hydrolytic actions. The synthetic 14 amino acids peptide analogue (i.e. “T14”), and subsequently the larger, more stable, and more potent amino acid sequence in which it is embedded (i.e. “T30”) display actions comparable to those reported for ‘non-cholinergic’ AChE, where the inert residue within the T30 sequence (i.e. “T15”) is without effect. Acute effects of T14 and T30 are that they:- (i) modulate calcium entry into neurons in brain slices over time scales from milliseconds to hours; (ii) compromise cell viability in PC 12 cells and also in neuronal organotypic cultures in vitro; (iii) modulate ‘compensatory’ calcium-induced AChE release from neurons and PC 12 cells; (iv) activate calcium currents in oocytes and neurons in brain slices; (v) synergise with amyloid in toxic effects; and (vi) are involved in amyloid precursor protein production and amyloid beta (Aβ) peptide release. Chronic effects of T14 and T30 are that they:- (i) reduce neuron growth; (ii) induce apoptosis; (iii) increase AChE release; (iv) bind to and modulate α7 nicotinic-receptor; and (v) enhance expression of the α7 receptor on the cell surface over 24 hours, thereby providing a feedforward mechanism for further toxicity. Since T14 and T30 are more selective than β-amyloid in inducing toxicity and are also synergistic with amyloid exacerbating toxicity, it has been postulated that any agent which blocks the toxic effects of T14 or T30 would also reduce the less selective and subsequent toxic effect of amyloid. The inventor has previously shown that T30 and T14 peptides bind to an allosteric site on the α7 nicotinic-receptor to induce a spectrum of trophic-toxic effects. This receptor is co-expressed with AChE during critical periods of brain development as well as showing a closely parallel distribution in the adult brain, and is one of the most powerful calcium ionophores in the brain. It can also function independent of cholinergic transmission, since choline (derived from diet) can serve as an alternative primary ligand. Moreover, this receptor has already been implicated in Alzheimer's disease as one of the targets for the current therapy galanthamine (Reminyl (RTM)), as well as being linked to the actions of amyloid. However, the efficacy of galanthamine has proved limited, whilst other α7 nicotinic acetylcholine receptor antagonists are still in clinical trials. Not only does galanthamine have non-specific effects on other receptors, as well as inhibiting AChE, but it has a low affinity for the α7 nicotinic-receptor (i.e. only 10 μM) compared to that of T30 and T14, which have much higher affinities for the α7 nicotinic-receptor (i.e.5 nM). Hence if, in an Alzheimer's brain, the endogenous equivalent of the T30 peptide is already occupying the respective receptor site, galanthamine would need to be given at non- physiological, high doses with inevitable side effects and most importantly, questionable efficacy. In WO 2016/083809, the inventors identified small linear peptides (i.e.4-14 amino acids in length) derived from the C-terminus of acetylcholinesterase (AChE), or cyclic variants thereof. The inventors identified several neuroprotective agents against T30 that showed some promise for treating neurodegenerative disorders. A particular example includes the linear peptide NBP613 (MVHWKA), which had previously shown to protect against the toxic effects of T30 when tested in PC12 cells. However, it would be desirable to provide compounds with improved biological activity and/or improved absorption, distribution, metabolism and excretion (ADME) properties. The present invention arose from the inventors work in attempting to identify such compounds. Thus, according to a first aspect of the invention, there is provided a peptide derivative of Formula (I):

wherein R¹ is H, a C_1-6 alkyl or COR⁹; one of R^2a and R^2b is H and the other is a C_2-8 alkyl or -L¹X¹R¹⁰; one of R^3a and R^3b is H and the other is H or a C_1-6 alkyl; one of R^4a and R^4b is H and the other is H or is an optionally substituted C_1-6 alkyl, wherein the alkyl is unsubstituted or substituted with an optionally substituted 5 to 10 membered heteroaryl, an optionally substituted C_6-10 aryl, an optionally substituted 3 to 10 membered heterocycle or an optionally substituted C_3-10 cycloalkyl; one of R^5a and R^5b is H and the other is

; one of R^6a and R^6b is H and the other is H or an optionally substituted C_1-8 alkyl, wherein the alkyl is unsubstituted or substituted with NH₂ or

one of R^7a and R^7b is H and the other is H or a C_1-6 alkyl; R⁸ is OH or NH₂; R⁹ is a C_1-6 alkyl; L¹ is a C_1-6 alkylene or is absent; X¹ is -S-, -O- or NH; R¹⁰ is H or is a C_1-6 alkyl; R¹¹ is a halogen, OR¹², NR¹²R¹³, SR¹², CN, NO₂, an optionally substituted C_1-6 alkyl, an optionally substituted C_6-10 aryl, an optionally substituted C_3-10 cycloalkyl, an optionally substituted 3 to 10 membered heterocycle or an optionally substituted 5 to 10 membered heteroaryl; R¹² and R¹³ are each independently H, an optionally substituted C_1-6 alkyl, an optionally substituted C_6-10 aryl, an optionally substituted C_3-10 cycloalkyl, an optionally substituted 3 to 10 membered heterocycle or an optionally substituted 5 to 10 membered heteroaryl; m is 0 or an integer between 1 and 6; and n is 0 or an integer between 1 and 4; or a pharmaceutically acceptable salt, solvate, complex, tautomer or polymorphic form thereof; with the proviso that the peptide derivative of Formula (I) is not:

. Advantageously, the inventors have shown that compounds of Formula (I) can protect against the toxic effects of T30. This strongly suggests that these compounds could be used to treat a neurodegenerative disorder, such as Alzheimer's disease. The term “alkyl” as used herein, unless otherwise specified, refers to a saturated straight or branched hydrocarbon. In certain embodiments, the alkyl group is a primary, secondary, or tertiary hydrocarbon. Unless otherwise specified, an optionally substituted alkyl group can be unsubstituted or substituted with one or more of halogen, oxo, CN, OR¹⁴, NR¹⁴R¹⁵, SR¹⁴, optionally substituted C_6-10 aryl, optionally substituted C_3-10 cycloalkyl, optionally substituted 3 to 10 membered heterocycle or optionally substituted 5 to 10 membered heteroaryl, wherein R¹⁴ and R¹⁵ are each independently H, an optionally substituted C_1-6 alkyl, an optionally substituted C_6-10 aryl, an optionally substituted C_3-10 cycloalkyl, an optionally substituted 3 to 10 membered heterocycle or an optionally substituted 5 to 10 membered heteroaryl. “Heteroaryl”, unless specified otherwise, refers to a monocyclic or bicyclic aromatic ring system in which at least one ring atom is a heteroatom. The term includes bicyclic groups where one of the rings is aromatic and the other is not. In some embodiments, the heteroaryl is a monocyclic 5 or 6 membered ring system in which at least one ring atom is a heteroatom. The or each heteroatom may be independently selected from the group consisting of oxygen, sulfur and nitrogen. The heteroaryl may contain 1, 2, 3 or 4 heteroatoms. Examples of 5 to 10 membered heteroaryl groups include furan, thiophene, indole, azaindole, oxazole, thiazole, isoxazole, isothiazole, imidazole, N- methylimidazole, pyridine, pyrimidine, pyrazine, pyrrole, N-methylpyrrole, pyrazole, N-methylpyrazole, 1,3,4-oxadiazole, 1,2,4-triazole, 1- methyl-1,2,4-triazole, 1H- tetrazole, 1-methyltetrazole, benzoxazole, benzothiazole, benzofuran, benzisoxazole, benzimidazole, N-methylbenzimidazole, azabenzimidazole, indazole, quinazoline, quinoline, and isoquinoline. Bicyclic 5 to 10 membered heteroaryl groups include those where a phenyl, pyridine, pyrimidine, pyrazine or pyridazine ring is fused to a 5 or 6- membered monocyclic heteroaryl ring. A heteroaryl group can be unsubstituted or substituted with one or more of halogen, oxo, CN, OR¹⁴, NR¹⁴R¹⁵, SR¹⁴, optionally substituted C_1-6 alkyl, optionally substituted C_6-10 aryl, optionally substituted C_3-10 cycloalkyl, optionally substituted 3 to 10 membered heterocycle or optionally substituted 5 to 10 membered heteroaryl, wherein R¹⁴ and R¹⁵ are each independently H, an optionally substituted C_1-6 alkyl, an optionally substituted C_6-10 aryl, an optionally substituted C_3-10 cycloalkyl, an optionally substituted 3 to 10 membered heterocycle or an optionally substituted 5 to 10 membered heteroaryl. “Aryl”, unless specified otherwise, refers to a monocyclic or bicyclic aromatic ring system in which all of the ring atoms are carbon. The term includes bicyclic groups where one of the rings is aromatic and the other is not. An optionally substituted aryl group may be an optionally substituted phenyl group. An optionally substituted aryl group can be unsubstituted or substituted with one or more of halogen, oxo, CN, OR¹⁴, NR¹⁴R¹⁵, SR¹⁴, optionally substituted C_1-6 alkyl, optionally substituted C_6-10 aryl, optionally substituted C_3-10 cycloalkyl, optionally substituted 3 to 10 membered heterocycle or optionally substituted 5 to 10 membered heteroaryl, wherein R¹⁴ and R¹⁵ are each independently H, an optionally substituted C_1-6 alkyl, an optionally substituted C_6-10 aryl, an optionally substituted C_3-10 cycloalkyl, an optionally substituted 3 to 10 membered heterocycle or an optionally substituted 5 to 10 membered heteroaryl. “Heterocycle” or “heterocyclyl”, unless specified otherwise, refers to a monocyclic, bicyclic or bridged molecule in which at least one ring atom is a heteroatom. The or each heteroatom may be independently selected from the group consisting of oxygen, sulfur and nitrogen. The heterocycle may contain 1, 2, 3 or 4 heteroatoms. A heterocycle may be saturated or partially saturated. Exemplary 3 to 8 membered heterocycle groups include but are not limited to aziridine, oxirane, oxirene, thiirane, pyrroline, pyrrolidine, dihydrofuran, tetrahydrofuran, dihydrothiophene, tetrahydrothiophene, dithiolane, piperidine, 1,2,3,6-tetrahydropyridine-1-yl, tetrahydropyran, pyran, morpholine, piperazine, thiane, thiine, piperazine, azepane, diazepane and oxazine. A heterocycle group can be unsubstituted or substituted with one or more of halogen, oxo, CN, OR¹⁴, NR¹⁴R¹⁵, SR¹⁴, optionally substituted C_1-6 alkyl, optionally substituted C_6-10 aryl, optionally substituted C_3-10 cycloalkyl, optionally substituted 3 to 10 membered heterocycle or optionally substituted 5 to 10 membered heteroaryl, wherein R¹⁴ and R¹⁵ are each independently H, an optionally substituted C_1-6 alkyl, an optionally substituted C_6-10 aryl, an optionally substituted C_3-10 cycloalkyl, an optionally substituted 3 to 10 membered heterocycle or an optionally substituted 5 to 10 membered heteroaryl. “Cycloalkyl”, unless otherwise specified, refers to a non-aromatic, saturated or partially saturated, monocyclic, bicyclic or polycyclic hydrocarbon ring system. Representative examples of a cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. A cycloalkyl group can be unsubstituted or substituted with one or more of halogen, oxo, CN, OR¹⁴, NR¹⁴R¹⁵, SR¹⁴, optionally substituted C_1-6 alkyl, optionally substituted C_6-10 aryl, optionally substituted C_3-10 cycloalkyl, optionally substituted 3 to 10 membered heterocycle or optionally substituted 5 to 10 membered heteroaryl, wherein R¹⁴ and R¹⁵ are each independently H, an optionally substituted C_1-6 alkyl, an optionally substituted C_6-10 aryl, an optionally substituted C_3-10 cycloalkyl, an optionally substituted 3 to 10 membered heterocycle or an optionally substituted 5 to 10 membered heteroaryl. In some embodiments, the peptide derivative of Formula (I) is a compound of Formula (Ia):

In some embodiments, R¹ is H. In preferred embodiments, R¹ is COR⁹. R⁹ may be a C_1-3 alkyl and is preferably methyl. Accordingly, R¹ may be COCH₃. Advantageously, R¹ changes the overall hydrophobicity of the peptide and also potentially adds metabolic stability. One of R^2a and R^2b may be H and the other may be a C3-6 alkyl. Accordingly, one of R^2a and R^2b may be H and the other may be n-propyl, n-butyl, n-pentyl or n-hexyl. Alternatively, one of R^2a and R^2b may be H and the other may be -L¹X¹R¹⁰. L¹ may be a C_1-6 alkylene, more preferably a C_1-3 alkylene. Accordingly, L¹ may be - CH₂-, -CH₂CH₂- or -CH₂CH₂CH₂-, and most preferably is CH₂CH₂-. X¹ may be S. R¹⁰ may be a C_1-6 alkyl, and more preferably is a C_1-3 alkyl. Accordingly, R¹⁰ may be methyl, ethyl or n-propyl, and is preferably methyl. Accordingly, one of R^2a and R^2b may be H and the other may be n-butyl or - CH₂CH₂SCH₃. In some embodiments, R^2a is H. Preferably, R^2b is n-butyl or -CH₂CH₂SCH₃. One of R^3a and R^3b may be H and the other may be a C_1-6 alkyl, a C_1-4 alkyl or a C_1-3 alkyl. Accordingly, one of R^3a and R^3b may be H and the other may be methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl or t-butyl. In some embodiments, one of R^3a and R^3b is H and the other is methyl or i-propyl. In some embodiments, R^3a is H. Preferably, R^3b is methyl or i-propyl. One of R^4a and R^4b may be H and the other may be an optionally substituted C_1-6 alkyl, wherein the alkyl is unsubstituted or substituted with an optionally substituted 5 to 10 membered heteroaryl, an optionally substituted C_6-10 aryl, an optionally substituted 3 to 10 membered heterocycle or an optionally substituted C_3-10 cycloalkyl. 9ore preferably one of R^4a and R^4b may be H and the other may be an optionally substituted C_1-3 alkyl, wherein the alkyl is unsubstituted or substituted with an optionally substituted 5 to 10 membered heteroaryl, an optionally substituted C_6-10 aryl, an optionally substituted 3 to 10 membered heterocycle or an optionally substituted C_3-10 cycloalkyl. In some embodiments, the optionally substituted alkyl is an optionally substituted methyl. In embodiments where the alkyl is substituted with an optionally substituted heteroaryl, an optionally substituted aryl, an optionally substituted heterocycle or an optionally substituted cycloalkyl, the heteroaryl, aryl, heterocycle or cycloalkyl may be unsubstituted or substituted with one or more substituents as specified above. Preferably, the heteroaryl, aryl, heterocycle or cycloalkyl may be unsubstituted or substituted with or more substituents selected from halogen, OR¹⁴, SR¹⁴, optionally substituted C_1-6 alkyl, optionally substituted phenyl, optionally substituted C_3-6 cycloalkyl, optionally substituted 3 to 6 membered heterocycle or optionally substituted 5 or 6 membered heteroaryl. More preferably, the heteroaryl, aryl, heterocycle or cycloalkyl may be unsubstituted or substituted with or more substituents selected from halogen, OR¹⁴, SR¹⁴ and optionally substituted methyl, wherein R¹⁴ is H or optionally substituted methyl and an optionally substituted methyl is unsubstituted or substituted with one or more halogens or a phenyl. The or each halogen may be fluorine, chlorine, bromine or iodine. In some embodiment, the alkyl may be unsubstituted. Alternatively, the alkyl may be substituted with an optionally substituted 5 or 6 membered heteroaryl, an optionally substituted phenyl, an optionally substituted 5 or 6 membered heterocycle or an optionally substituted C_5-6 cycloalkyl. More preferably, the alkyl may be substituted with an optionally substituted 5 or 6 membered heteroaryl. The heteroaryl may be pyrrolyl, pyrazolyl, imidazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl or tetrazolyl. Accordingly, the heteroaryl may be

, where p is 0 or an integer between 1 and 3 and R¹⁶ is halogen, oxo, CN, OR¹⁴, NR¹⁴R¹⁵, SR¹⁴, optionally substituted C_1-6 alkyl, optionally substituted C_6-10 aryl, optionally substituted C_3-10 cycloalkyl, optionally substituted 3 to 10 membered heterocycle or optionally substituted 5 to 10 membered heteroaryl. R¹⁶ is preferably as defined above in relation to the optional substituents of the heteroaryl, aryl, heterocycle or cycloalkyl. In some embodiments, p is 0. Alternatively, p may be 1, 2 or 3. Accordingly, the heteroaryl may be

or

Accordingly, one of R^4a and R^4b may be H and the other may be methyl or

. In some embodiments, one of R^4a and R^4b may be H and the other may be methyl or

In some embodiments, R^4a is H. Preferably, R^4b is methyl or

In some embodiments, m is 0. In other embodiments, m is an integer between 1 and 6. Accordingly, m may be 1, 2, 3, 4, 5 or 6. In some embodiments, m is 0 or 1. Accordingly, one of R^5a and R^5b may be H and the other may be

R¹¹ may be a halogen, OR¹², NR¹²R¹³, SR¹², an optionally substituted C_1-6 alkyl, an optionally substituted C_6-10 aryl, an optionally substituted C_3-10 cycloalkyl, an optionally substituted 3 to 10 membered heterocycle or an optionally substituted 5 to 10 membered heteroaryl. More preferably, R¹¹ may be a halogen, OR¹², SR¹², an optionally substituted C_1-3 alkyl, an optionally substituted phenyl, an optionally substituted C_3-6 cycloalkyl, an optionally substituted 3 to 6 membered heterocycle or an optionally substituted 5 or 6 membered heteroaryl. Most preferably, R¹¹ may be halogen, OR¹², SR¹² and optionally substituted methyl, wherein R¹² is H or optionally substituted methyl and an optionally substituted methyl is unsubstituted or substituted with one or more halogens or a phenyl. The halogen may be fluorine, chlorine, bromine or iodine. n may be 1, 2 or 3, and is preferably 1. Accordingly, one of R^5a and R^5b may be H and the other may be

In some embodiments, R^5a is H. Preferably, R^5b is

In alternative embodiments, R^5b is H. Preferably, R^5a is

. Preferably, one of R^6a and R^6b is H and the other is an optionally substituted C_1-8 alkyl, wherein the alkyl is unsubstituted or substituted with NH₂ or

. More preferably, one of R^6a and R^6b is H and the other is an optionally substituted C_1-6 alkyl, wherein the alkyl is unsubstituted or substituted with NH₂ or

. Most preferably, one of R^6a and R^6b is H and the other is an optionally substituted C_1-4 alkyl, wherein the alkyl is unsubstituted or substituted with NH₂ or

Accordingly, one of R^6a and R^6b may be H and the other may be an optionally substituted methyl, an optionally substituted ethyl, an optionally substituted n-propyl, an optionally substituted n-butyl, an optionally substituted n-pentyl or an optionally substituted n-hexyl, wherein the alkyl is unsubstituted or substituted with NH₂ or

. In some embodiments, one of R^6a and R^6b is H and the other is methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl,

, , , or

In some embodiments, R^6a is H. Preferably, R^6b is methyl,

, or

.

In other embodiments, R^6b is H. Preferably, R^6a is methyl,

, or

.

One of R^7a and R^7b may be H and the other may be a C_1-6 alkyl. More preferably, one of R^7a and R^7b may be H and the other may be a C_1-3 alkyl. Accordingly, one of R^7a and R^7b may be H and the other may be methyl, ethyl or propyl and is preferably methyl. In some embodiments, R^7a is H. Preferably, R^7b is methyl. R⁸ may be NH₂. In some preferred embodiments, R⁸ is OH. In some embodiments, the peptide derivative of Formula (I) may be a peptide derivative of Formula (101) to (117):

In a second aspect, there is provided a pharmaceutical composition comprising the peptide derivative of the first aspect and a pharmaceutically acceptable carrier. The pharmaceutical composition is preferably an anti-neurodegenerative disease composition, i.e. a pharmaceutical formulation used in the therapeutic amelioration, prevention or treatment of a neurodegenerative disorder in a subject, such as Alzheimer's disease. In a third aspect, there is provided the peptide derivative according to the first aspect or a pharmaceutical composition according to the second aspect, for use in therapy or diagnosis. In a fourth aspect, there is provided the peptide derivative according to the first aspect or a pharmaceutical composition according to the second aspect, for use in treating, ameliorating or preventing a neurodegenerative disorder. In a fifth aspect of the invention, there is provided a method of treating, ameliorating or preventing a neurodegenerative disorder in a subject, the method comprising, administering to a subject in need of such treatment, a therapeutically effective amount of the peptide derivative according to the first aspect or the pharmaceutical composition of the second aspect. The neurodegenerative disorder which is treated is preferably one which is characterised by the damage or death of 'Global' neurons. For example, the neurodegenerative disorder may be selected from a group consisting of Alzheimer's disease; Parkinson's disease; Huntington's disease; motor neurone disease; Spinocerebellar ataxia (SCA) type 1, type 2, and type 3; Amyotrophic Lateral Sclerosis (ALS); schizophrenia; Lewy-body dementia; and Frontotemporal Dementia. Preferably, the neurodegenerative disorder, which is treated, is Alzheimer's disease, Parkinson's disease, or Motor Neurone disease. Most preferably, the neurodegenerative disorder, which is treated is Alzheimer's disease. It will be appreciated that peptide derivatives according to the invention may be used in a medicament which may be used in a monotherapy for treating, ameliorating, or preventing neurodegenerative disorder, such as Alzheimer's disease. Alternatively, the peptide derivative according to the invention may be used as an adjunct to, or in combination with, known therapies for treating, ameliorating, or preventing Alzheimer's disease, such as acetylcholinesterase inhibitors. The peptide derivatives according to the invention may be combined in compositions having a number of different forms depending, in particular, on the manner in which the composition is to be used. Thus, for example, the composition may be in the form of a powder, tablet, capsule, liquid, ointment, cream, gel, hydrogel, aerosol, spray, micellar solution, transdermal patch, liposome suspension or any other suitable form that may be administered to a person or animal in need of treatment. It will be appreciated that the vehicle of medicaments according to the invention should be one which is well-tolerated by the subject to whom it is given, and preferably enables delivery of the peptide across the blood-brain barrier. It will be appreciated that the efficiency of any treatment for brain disorders depends on the ability of the candidate therapeutic peptide derivative to cross the blood-brain barrier (BBB). However, it is well-known that, during Alzheimer's disease, the blood- brain barrier increases in permeability that could allow the peptide derivatives of the invention to reach the central nervous system, indeed ideally only at the sites of degeneration where it is needed, i.e. where the BBB is compromised. Two main strategies may be applied to cross the BBB with peptide derivatives of the invention, including: (1) use of nanoparticles as transporters to specifically target the brain and deliver the active compound. This method has successfully been used to deliver peptides, proteins and anticancer drugs to the brain; (2) use of cargo peptides. The addition of such a peptide specifically transported across the BBB allows the transfer of the peptide derivatives of the invention through a facilitated manner. Medicaments comprising peptide derivatives according to the invention may be used in a number of ways. For instance, oral administration may be required, in which case the peptide derivative may be contained within a composition that may, for example, be ingested orally in the form of a tablet, capsule or liquid. An alternative option for administrating the peptide derivatives would be to use a nasal spray, since administration by nasal spray reaches the brain faster and more efficiently than oral or intravenous ways of administration (see http://memoryzine.com/2010/07/26/nose- sprays-cross-blood-brain-barrier-faster-and-safer/ and Greenfield et al. Alzheimers Dement (N Y).2022; 8(1): e12274). Hence, compositions comprising peptide derivatives of the invention may be administered by inhalation (e.g. intranasally). Compositions may also be formulated for topical use. For instance, creams or ointments may be applied to the skin, for example, adjacent the brain. Peptide derivatives according to the invention may also be incorporated within a slow- or delayed-release device. Such devices may, for example, be inserted on or under the skin, and the medicament may be released over weeks or even months. The device may be located at least adjacent the treatment site, e.g. the head. Such devices may be particularly advantageous when long-term treatment with peptide derivatives used according to the invention is required and which would normally require frequent administration (e.g. at least daily injection). In a preferred embodiment, medicaments according to the invention may be administered to a subject by injection into the blood stream or directly into a site requiring treatment. For example, the medicament may be injected at least adjacent the brain. Injections may be intravenous (bolus or infusion) or subcutaneous (bolus or infusion), or intradermal (bolus or infusion). It will be appreciated that the amount of the peptide derivative that is required is determined by its biological activity and bioavailability, which in turn depends on the mode of administration, the physiochemical properties of the peptide derivative and whether it is being used as a monotherapy or in a combined therapy. The frequency of administration will also be influenced by the half-life of the peptide derivative within the subject being treated. Optimal dosages to be administered may be determined by those skilled in the art, and will vary with the particular peptide derivative in use, the strength of the pharmaceutical composition, the mode of administration, and the advancement of the neurodegenerative disease. Additional factors depending on the particular subject being treated will result in a need to adjust dosages, including subject age, weight, gender, diet, and time of administration. Generally, a daily dose of between 0.001µg/kg of body weight and 10mg/kg of body weight of the peptide derivative according to the invention may be used for treating, ameliorating, or preventing neurodegenerative disease, depending upon which peptide derivative is used. More preferably, the daily dose is between 0.01μg/kg of body weight and 1mg/kg of body weight, and most preferably between approximately 0.1μg/kg and 10μg/kg body weight. The peptide derivative may be administered before, during or after onset of neurodegenerative disease. Daily doses may be given as a single administration (e.g. a single daily injection or inhalation of a nasal spray). Alternatively, the peptide derivative may require administration twice or more times during a day. As an example, the peptide derivative may be administered as two (or more depending upon the severity of the neurodegenerative disease being treated) daily doses of between 0.07 μg and 700 mg (i.e. assuming a body weight of 70 kg). A patient receiving treatment may take a first dose upon waking and then a second dose in the evening (if on a two dose regime) or at 3- or 4-hourly intervals thereafter. Alternatively, a slow release device may be used to provide optimal doses of the peptide derivative according to the invention to a patient without the need to administer repeated doses. Known procedures, such as those conventionally employed by the pharmaceutical industry (e.g. in vivo experimentation, clinical trials, etc.), may be used to form specific formulations of the peptide derivative according to the invention and precise therapeutic regimes (such as daily doses of the agents and the frequency of administration). A “subject” may be a vertebrate, mammal, or domestic animal. Hence, medicaments according to the invention may be used to treat any mammal, for example livestock (e.g. a horse), pets, or may be used in other veterinary applications. Most preferably, however, the subject is a human being. A “therapeutically effective amount” of the peptide derivative is any amount which, when administered to a subject, is the amount of active agent that is needed to treat the neurodegenerative disorder condition, or produce the desired effect. For example, the therapeutically effective amount of the peptide derivative used may be from about 0.001 mg to about 800 mg, and preferably from about 0.01 mg to about 500 mg. It is preferred that the amount of the peptide derivative is an amount from about 0.1 mg to about 100 mg. A “pharmaceutically acceptable vehicle” as referred to herein, is any known compound or combination of known compounds that are known to those skilled in the art to be useful in formulating pharmaceutical compositions. In one embodiment, the pharmaceutically acceptable vehicle may be a solid, and the composition may be in the form of a powder or tablet. A solid pharmaceutically acceptable vehicle may include one or more substances which may also act as flavouring agents, lubricants, solubilisers, suspending agents, dyes, fillers, glidants, compression aids, inert binders, sweeteners, preservatives, coatings, or tablet- disintegrating agents. The vehicle may also be an encapsulating material. In powders, the vehicle is a finely divided solid that is in admixture with the finely divided active agents according to the invention. In tablets, the active agent may be mixed with a vehicle having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active agents. Suitable solid vehicles include, for example calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins. In another embodiment, the pharmaceutical vehicle may be a gel and the composition may be in the form of a cream or the like. However, the pharmaceutical vehicle may be a liquid, and the pharmaceutical composition is in the form of a solution. Liquid vehicles are used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions. The active agent according to the invention may be dissolved or suspended in a pharmaceutically acceptable liquid vehicle such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats. The liquid vehicle can contain other suitable pharmaceutical additives such as solubilisers, emulsifiers, buffers, preservatives, sweeteners, flavouring agents, suspending agents, thickening agents, colours, viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid vehicles for oral and parenteral administration include water (partially containing additives as above, e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil). For parenteral administration, the vehicle can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid vehicles are useful in sterile liquid form compositions for parenteral administration. The liquid vehicle for pressurized compositions can be a halogenated hydrocarbon or other pharmaceutically acceptable propellant. Liquid pharmaceutical compositions, which are sterile solutions or suspensions, can be utilized by, for example, intramuscular, intrathecal, epidural, intraperitoneal, intravenous and particularly subcutaneous injection. The peptide derivative may be prepared as a sterile solid composition that may be dissolved or suspended at the time of administration using sterile water, saline, or other appropriate sterile injectable medium. The peptide derivative and compositions of the invention may be administered orally in the form of a sterile solution or suspension containing other solutes or suspending agents (for example, enough saline or glucose to make the solution isotonic), bile salts, acacia, gelatin, sorbitan monoleate, polysorbate 80 (oleate esters of sorbitol and its anhydrides copolymerized with ethylene oxide) and the like. The peptide derivative used according to the invention can also be administered orally either in liquid or solid composition form. Compositions suitable for oral administration include solid forms, such as pills, capsules, granules, tablets, and powders, and liquid forms, such as solutions, syrups, elixirs, and suspensions. Forms useful for parenteral administration include sterile solutions, emulsions, and suspensions. All of the features described herein (including any accompanying claims, abstract and drawings), and/or all of the steps of any method or process so disclosed, may be combined with any of the above aspects in combination, except combinations where at least some of such features and/or steps are mutually exclusive. For a better understanding of the invention, and to show how embodiments of the same may be carried into effect, reference will now be made, by way of example, to the accompanying Figures, in which:- Figure 1 shows data for a peptide (NBP613). The data show that NBP613 (4µM) does not induce a significant increase in Basal forebrain (BF)-evoked activity when co- perfused with T30 (n=12) but shows a strong recovering trend. Data are indicated as the mean ± SEM. *p≤0.05; Figure 2 shows data for a peptide variant (NBP613A), where the N-terminus of the ^{peptide has been acetylated. The data show that NBP613A (4µM) does not induce a} significant increase in BF-evoked activity when co-perfused with T30 (n=10). Data are indicated as the mean ± SEM; Figure 3 shows data for a peptide variant (NBP613B), where the C-terminus of the peptide has been converted from an acid to an amine. The data show that NBP613B (4µM) does induce a significant increase in BF-evoked activity when co-perfused with T30 (n=13). Data are indicated as the mean ± SEM * p≤0.05, **p≤0.01; Figure 4 shows data for a peptide variant (NBP613C), where the N-terminus of the peptide has been acetylated and the C-terminus of the peptide has been converted from an acid to an amine. The data show that NBP613C (4µM) does induce a significant increase in BF-evoked activity when co-perfused with T30 (n=15). Data are indicated as the mean ± SEM. * p≤0.05; Figure 5 shows data for a peptide variant (NBP613D), where the methionine (M) residue within the original peptide has been converted to a norleucine. The data show that NBP613D (4µM) does not induce a recovery in BF-evoked activity when co- perfused with T30 (n=11). Data are indicated as the mean ± SEM * p≤0.05; Figure 6 shows data for a peptide variant (NBP613E), where the N-terminus of the peptide has been acetylated and the methionine (M) residue within the original peptide has been converted to a norleucine. The data show that NBP613E (4µM) does not induce a recovery in BF-evoked activity when co-perfused with T30 (n=12). Data are indicated as the mean ± SEM **p≤0.01; Figure 7 shows data for a peptide variant (NBP613G), where the N-terminus of the peptide has been acetylated, the C-terminus of the peptide has been converted from an acid to an amine and the methionine (M) residue within the original peptide has been converted to a norleucine. The data show that NBP613G (4µM) induces a recovery in BF-evoked activity when co-perfused with T30 (n=13). Data are indicated as the mean ± SEM * p≤0.05; Figure 8 shows data for a peptide variant (613Peptide1) where the lysine (K) residue from the original peptide has been converted to alanine (A). The data show that 613Peptide1 (4µM) induces a recovery in BF-evoked activity when co-perfused with T30 (n=12). Data are indicated as the mean ± SEM * p≤0.05; Figure 9 shows data for a peptide variant (613Peptide2) where the tryptophan (W) residue from the original peptide has been converted to alanine (A). The data show that 613Peptide2 (4µM) does not induce a recovery in BF-evoked activity when co- perfused with T30 (n=11). Data are indicated as the mean ± SEM * p≤0.05; Figure 10 shows data for a peptide variant (613Peptide3) where the histidine (H) residue from the original peptide has been converted to alanine (A). The data show that 613Peptide3 (4µM) induces a recovery in BF-evoked activity when co-perfused with T30 (n=12). Data are indicated as the mean ± SEM * p≤0.05; Figure 11 shows data for a peptide variant (613Peptide4) where the valine (V) residue from the original peptide has been converted to alanine (A). The data show that 613Peptide4 (4µM) induces a recovery in BF-evoked activity when co-perfused with T30 (n=12). Data are indicated as the mean ± SEM * p≤0.05; Figure 12 shows data for a peptide variant (613Peptide5) where the methionine (M) residue from the original peptide has been converted to alanine (A). The data show that 613Peptide5 (4µM) does not induce a significant recovery in BF-evoked activity when co-perfused with T30 (n=11). Data are indicated as the mean ± SEM; Figure 13 shows data for a peptide-peptoid hybrid (Peptoid1) where the lysine (K) residue from the original peptide has been modified. The data show that Peptoid1 (4µM) induces a recovery in BF-evoked activity when co-perfused with T30 (n=12). Data are indicated as the mean ± SEM * p≤0.05, **p≤0.01; Figure 14 shows AChE response when PC12 cells injected with NBP613A, NBP613C or NBP613G (+ T14, 250nM) at 10nM and 100nM. Data are indicated as the mean ± SEM. **p≤0.01; Figure 15 shows data for modified peptides (Rscan peptides) where the lysine (K) residue from the original peptide has been replaced with an arginine (R) and either there is an amine at the N-terminus and an acid at the C-terminus (Rscan Acid), there is an amine at the N-terminus and an amide at the C-terminus (Rscan Amide) or there is an acyl group at the N-terminus and an amide at the C-terminus (Rscan Acetyl). The data show the AChE response when PC12 cells injected with Rscan peptides (+ T14, 250nM) at 10nM and 100nM. Data are indicated as the mean ± SEM. ***p≤0.001; Figure 16 shows calcium response when PC12 cells injected with NBP613A, NBP613C or NBP613G (+ T14, 250nM) at 10nM and 100nM. Data are indicated as the mean ± SEM. **p≤0.01; Figure 17 shows calcium response when PC12 cells injected with Rscan peptides (+ T14, 250nM) at 10nM and 100nM. Data are indicated as the mean ± SEM. ***p≤0.00.1; Figure 18 shows viability of PC12 cells injected with NBP613A, NBP613C or NBP613G (+ T14, 250nM) at 10nM and 100nM. Data are indicated as the mean ± SEM Figure 19 shows viability of PC12 cells injected with Rscan peptides (+ T14, 250nM) at 10nM and 100nM. Data are indicated as the mean ± SEM. *p≤0.05; Figure 20 shows data for modified peptides where the lysine (K) residue from the original peptide has been replaced with an arginine (R), the N-terminus of the peptide has been acetylated and either the methionine (M) residue within the original peptide has been converted to a norleucine (2022-pep-1, NBP6A) or the methionine (M) residue has not been altered (2022-pep-2, NBP6B). The data show the effects of NBP6A and NBP6B on calcium influx, cell viability and AChE release when applied alone (to test the toxicity). Data are indicated as the mean ± SEM; Figure 21 shows the inhibiting effects of different doses of NBP6A on T14-induced calcium influx (left panel), T14-induced cell toxicity (middle panel) and T14-induced AChE release (right panel), in 3–5 replicates of PC12 cells (mean ± SEM). These three cell-based parameters are expressed as % of untreated control cells. A one-way ANOVA (“factor” dose) tests were used for statistics followed by Dunnett post-hoc tests to determine the significance of each drug at different doses in comparison to T14 induced changes #: P<0.05; ##: P<0.01; ###: P<0.001; ####: P<0.0001. A one-sample t-test was used to determine whether T14 induced changes were significantly different than control. *: P<0.05; **: P<0.01; ***: P<0.001; ****: P<0.0001; and T14 # p < 0.05, ## p < 0.001, ### p < 0.0005, and #### p < 0.0001; Figure 22 shows the inhibiting effects of different doses of NBP6B on T14-induced calcium influx (left panel), T14-induced cell toxicity (middle panel) and T14-induced AChE release (right panel), in 3–5 replicates of PC12 cells (mean ± SEM). These three cell-based parameters are expressed as % of untreated control cells. A one-way ANOVA (“factor” dose) tests were used for statistics followed by Dunnett post-hoc tests to determine the significance of each drug at different doses in comparison to T14 induced changes #: P<0.05; ##: P<0.01; ###: P<0.001; ####: P<0.0001. A one-sample t-test was used to determine whether T14 induced changes were significantly different than control. *: P<0.05; **: P<0.01; ***: P<0.001; ****: P<0.0001; and T14 # p < 0.05, ## p < 0.001, ### p < 0.0005, and #### p < 0.0001; and Figure 23 shows the effect of NBP6B treatment on the basal forebrain-evoked activity based upon VSDI data. Data are indicated as the mean ± SEM. *p≤0.05 and ***p≤0.00.1. Examples Example 1 – NBP613 peptide derivatives The inventors have previously shown that NBP613 (MVHWKA) (SEQ ID No:1) protects against the effects of T30, a toxic peptide, see WO 2016/083809. In order to improve the biological activity and absorption, distribution, metabolism and excretion (ADME) properties, the inventors produced a series of NBP613 peptide derivatives. More specifically, the inventors modified the N-terminus, the C-terminus of NBP613 and/or the methionine residue with a view to change the overall hydrophobicity of the peptide, and/or improve the metabolic stability of the peptide. The structures of the NBP613 peptide derivatives are shown in Table 1. Table 1: NBP613 and derivatives thereof

The neuroprotective effect of the NBP613 peptide and the derivatives against T30 was determined by using voltage-sensitive dye imaging (VSDI) in brain slices containing the basal forebrain (BF), see Figures 1-7. The data show separate control and test recordings of brain slices containing the basal forebrain continuously perfused with artificial cerebrospinal fluid (aCSF). Space-time maps reveal neuronal activity of BF population represented by histograms of summed fluorescence. When T30 is administered, a significant reduction in basal forebrain (BF)-evoked activity is detectable. When T30 is co-administered with a protective compound, it is expected a significant recovery of BF-evoked signal will be observed, suggesting that the compound, is able to block T30-induced toxicity. As shown in Figure 1, when the original NBP613 peptide is used recovery of BF-evoked signal is observed, but the effect is No significant recovery in BF-evoked activity was observed when NBP613A, NBP613D and NBP613E were co-administered with T30, compared to administering T30 alone (Figures 2, 5 and 6). Although, the figures appear to show some recovery for NBP613A and NBP613E. When NBP613B, NBP613C and NBP613G were co-administered with T30, a significant recovery in BF-evoked activity was observed, compared to administering T30 alone (Figures 3, 4 and 7). These results show that NBP613B, NBP613C and NBP613G were successful in protecting against the effects of T30. NBP613F was not tested. Example 2 – Alanine scan peptides derived from NBP613 To provide further insights into the essential components of this specific peptide, a series of alanine scan peptides derived from NBP613 were designed. These are shown in Table 2 below. Table 2: Alanine scan peptides derived from NBP613

The neuroprotective effects of the alanine scan peptides against T30 were evaluated by using VSDI in brain slices containing the basal forebrain (Figures 8-12). The results shows that 613Peptide1, 613Peptide3, and 613Peptide4 were able to induce a recovery in BF-evoked activity, compared to administering T30 alone (Figures 8, 10 and 11). Accordingly, substitution of lysine (K), histidine (H) or valine (V) for alanine (A) in the NBP613 peptide sequence did not affect the biological activity of the NBP613 peptide. However, 613Peptide2 and 613Peptide5 did not induce a significant recovery in BF- evoked activity, compared to administering T30 alone (Figures 9 and 12). Accordingly, substitution of tryptophan (W) or methionine (M) in the NBP613 peptide sequence for alanine was detrimental to the biological activity of NBP613. Example 3 – NBP613 peptide-peptoid hybrid Based on the results of 613Peptide 1, the inventors have shown that substitution of lysine (K) for alanine (A) in NBP613 did not affect the biological activity of the peptide. As such, the inventors designed a peptide-peptoid hybrid based upon NBP613, where the lysine residue was modified to be a peptoid type residue (Peptoid1). The resulting peptide-peptoid hybrid is shown below:

The protective effects of Peptoid1 against T30 was evaluated by using VSDI in brain slices containing the basal forebrain. The results show that when Peptoid1 was co- administered with T30, a significant recovery in BF-evoked activity was observed, compared to administration with T30 alone (Figure 13). Example 4 – Second generation compounds As mentioned above, the inventors have shown that substitution of lysine (K) for alanine (A) in NBP613 did not affect the biological activity of the peptide. Based upon this, the inventors synthesised a series of peptide derivatives based upon NBP613, NBP613B and NBP613C wherein the lysine residue (K) has been substituted with arginine I. The resulting peptides are shown in Table 3 below. Table 3: Arginine derivatives of NBP613

The neuroprotective effects of the NBP613 peptide derivatives (NBP613A, NBP613C and NBP613G) and the Rscan peptides against T14 was determined by using three in vitro systems: (i) AChE release from PC12 cells (Figures 14 and 15); (ii) calcium influx into PC12 cells (Figures 16 and 17); and (iii) PC12 cell viability (Figures 18 and 19). The AChE activity assay shows that treatment with T14 alone significantly increases the AChE activity in PC12 cells compared to the control. However, no significant difference in AChE activity compared to the control was observed when T14 was co-administered with the NBP613 peptides derivatives (Figure 14) or the Rscan peptides (Figure 15). Similarly, the calcium assay shows that treatment with T14 significantly increases calcium influx in PC12 cells compared to the control. However, no significant difference in calcium influx was observed compared to the control when T14 was co-administered with the NBP613 peptide derivatives (Figure 16) or the Rscan peptides (Figure 17). The cell viability assay qualitatively measures the number of viable cells by using a water-soluble tetrazolium salt (WST-8), which produces an orange formazan dye (WST-8 formazan) upon reduction by dehydrogenases in a cell. The amount of the coloured formazan dye generated by dehydrogenases in cells is directly proportional to the number of living cells. The results show that, compared to a control, cell viability was reduced when T14 was administered alone. Conversely, when T14 was co- administered with the NBP613 peptide derivatives (Figure 18) or the Rscan peptides (Figure 19), the viability was better than when administered with T14 alone, and for some compounds was the same as for the control. The above tests indicate that all of the NBP613 peptides derivatives and the Rscan peptides tested are blocking the toxic effects of T14. The NBP613 peptide derivatives and the Rscan peptides were each ranked in terms of their efficacy using Equation 1 below, which incorporates the mean results from all three of the in vitro systems tested above.

The peptides are ranked highest if they are closest to the standardised control conditions, i.e. the closer to the value of 2 they are the higher they are ranked. The results are provided in Tables 4 to 7 below. Table 4: Efficacy values obtained using Equation 1 for NBP613A, NBP613C and NBP613G

Table 5: Efficacy values obtained using Equation 1 for Rscan Acid, Rscan Amide and Rscan Acetyl

Table 6: Ranking order of NBP613A, NBP613C, NBP613G, Rscan Acid, Rscan Amide and Rscan Acetyl, when tested at 10 nM

Table 7: Ranking order of NBP613A, NBP613C, NBP613G, Rscan Acid, Rscan Amide and Rscan Acetyl, when tested at 100nM

As shown in Tables 6 and 7, the inventors found that NBP613C ranked the best when the peptides were tested at 10nM, and NBP613G ranked the best when the peptides were tested at 100nM. At both peptide concentrations (i.e.10nM and 100nM), Rscan Amide ranked the lowest, i.e. shows the least similarity to the control condition, and hence is least effective at reversing the effects of T14. These results demonstrate that at both peptide concentrations (i.e.10nM and 100nM), Rscan Acid shows greater efficacy than Rscan Amide. Accordingly, for the Rscan peptides, compounds with an acid group at the C-terminus are more active than compounds with an amide group. Example 5 – Third Generation Compounds As discussed above a comparison of the data for the Rscan Acid and Rscan Amide compounds indicates that compounds with a carboxylic acid group at the C-terminus are more active than compounds with an amide group. Based upon this, the inventors designed two further peptides: NBP6A and NBP6B. In both compounds, the N-terminus has been acetylated and the lysine residue (K) has been substituted for arginiI(R). Additionally, in NBP6A the methionine (M) residue has been substituted for norleucine. The structures of both compounds are shown below:

Cellular responses to NBP6A and NBP6B were determined by using three in vitro systems: (i) calcium influx into PC12 cells; (ii) PC12 cell viability; and (iii) AChE release from PC12 cells (Figure 20). The results show that no significant differences in calcium influx, cell viability or AChE release were observed following treatment with 2022 NBP6A and NBP6B alone, as compared to the control group. Using the same three in vitro systems mentioned above, the inventors then determined the protective effects of NBP6A and NBP6B against T14. Both NBP6A and NBP6B were tested in the range of concentrations of 0.1-50 nM(Figure 20-22). Administering T14 alone results in: (i) a significant increase in calcium influx; (ii) a significant decrease in cell viability; and (iii) a significant increase in AChE release. A strong recovering trend in the levels of calcium influx was observed for both NBP6A and NBP6B, although only the data for high dose NBP6B was found to be statistically significantly. Cell viability was observed to improve for both NBP6A and NBP6B, and a significantly higher cell viability was determined for NBP6A at 50nM and NBP6B at 5nM. Both NBP6A and NBP6B also resulted in a significantly lower AChE release. As would be expected, the results were less pronounced for low dosing conditions. The NBP6A and NBP6B were ranked in terms of their efficacy using Equation 1 when tested under both dosing conditions. The inventors found that NBP6B ranked the best when tested at both high and low dosage concentrations. Table 8: Ranking order of NBP6A and NBP6B at high doses

Table 9: Ranking order of NBP6A and NBP6B at low doses

The inventors then compared the efficacy of NBP6A and NBP6B to NBP14. NBP14 is a cyclic peptide with SEQ ID No: 20, as follows AEFHRWSSYWVHWK (SEQ ID No: 20) The structure is provided below:

NBP14 is described in more detail in WO 2015/004430 A9. In particular, the inventors compared the ratio needed of the receptor blocker to T14 to fully reverse the effects of T14 for each of calcium influx, cell viability and AChE release, and the results are provided in Table 10. Of particular note, NBP6A and NBP6B were respectively 50 and 100 times more potent at blocking the calcium influx induced by the administration of T14 compared to NBP14 (see table 10). Table 10: Ratio needed for full reversal of toxicity (mean = 100%) of antagonist vs T14 for NBP14, NBP6A and NBP6B.

The protective effects of NBP6B against T30 was evaluated by using VSDI in brain slices containing the basal forebrain. The results show that when NBP6B was co- administered with T30, a significant recovery in BF-evoked activity was observed, compared to administration with T30 alone (Figure 23). Example 6 – Further Peptide-Peptoid hybrids The inventors synthesised the following peptide-peptoid hybrids:

It is expected that the above compounds will also be to reverse the effects of T14. Materials and Methods Synthesis Peptides Peptides were synthesised using solid phase peptide synthesis (SPPS), the general scheme is shown below. Scheme 1: General scheme for solid phase peptide synthesis

Automated SPPS was carried out on a CEM Liberty Blue single channel microwave peptide synthesizer. All reactions were carried out in a 30 mL PTFE reaction vessel on a 0.1 mmol scale with agitation by bubbling nitrogen. Couplings used Fmoc-protected amino acid (5 equivalents), DIC activator (10 equivalents, 1M in DMF) and oxyma (5 equivalents, 1M in DMF) and were carried out for 4 minutes 40 seconds microwave assisted at 90°C and 10 W power . All couplings were double coupled apart from the following exceptions; Histidine residues were single coupled at 50°C for 10 minutes and Arginine residues were double coupled at 75°C. Deprotections were carried out with 20% piperidine in DMF for 1.35 minutes with DMF washes after each step. Peptide-Peptoid Hybrids To generate peptide-peptoid hybrids, generally the submonomer approach was used (Scheme 2) for the incorporation of peptoid monomers. This approach is a well- established and is compatible with Fmoc SPPS used for the synthesis of the rest of the sequence (See R. N. Zuckermann, J. M. Kerr, S. B. H. Kent and W. H. Moos, Journal of the American Chemical Society, 1992, 114, 10646–10647). Scheme 2: General submonomer approach for synthesis of peptoids

Resin (0.1 mmol unless stated otherwise) was pre-swollen in DMF (2 mL) for 30 minutes at RT in a polypropylene solid phase extraction cartridge (20 mL, fitted with two polypropylene frits). Single couplings were carried out using 4 equivalents of amino acid, DIC, HOBt and DIPEA in 2 mL of DMF, shaken for 1 hour. Reaction solution drained and resin washed with DMF (3 x 2 mL). Fmoc deprotection was carried out using 20% piperidine in DMF for 10 minutes whilst being shaken, this was then repeated. The deprotection solution was then drained and the resin washed with DMF (3 x 2 mL). Peptoid monomers were added following Fmoc deprotection of the preceding amino acid. A solution of bromoacetic acid (1 mL, 1 M) in DMF and DIC (0.2 mL) was added and shaken for 30 minutes at rt. The solution was then drained and the resin washed with DMF (3 x 2 mL). Amine (1 mL, 1 M) in DMF was added to the resin and shaken for 1 hour at rt. The reaction was drained and the resin washed with DMF (3 x 2 mL). Arginine-type Peptoid Monomers Following a deprotected amino acid, bromoacetic acid (1 mL, 1 M) in DMF and DIC (0.2 mL) was added to the resin and agitated for 30 minutes. Then 1,4 butane diamine (0.15 mL, 1.5 M) in DMF was added to the resin and agitated for a further hour. The resin was then washed with DMF (2 mL x3). Protection of the lysine-type peptoid monomer was achieved by addition of Dde-OH (0.18 g, 10 eq) in minimum DMF and agitated for 1 hour. The resin was then washed with DMF (2 mL x3). Then subsequent addition of amino acid or peptoid monomers were added following the methods described above under the heading “Peptide-Peptoid Hybrids”. Before cleavage of the complete sequence from the resin, Dde deprotection was performed using 2% hydrazine in DMF (4 x 4 mL x 3 minutes), with DMF washes (2 mL x3) between each repeat. The free amine was guadinilayted using 1H pyrazole 1- carboximodamide hyrdochloride (0.09 g, 6 eq) with DIPEA (0.2 ml, 12 eq) in the minimum volume of DMF and agitated for 1 hour at 40 °C . The guadinlaytion step was repeated a total of three times with DMF washes (2 mL x3) between each repeat. N-terminus Acetylation The N-terminus of the complete peptide sequence was acetylated using the swollen resin.20% acetic anhydride in DMF (5 mL) was added to the resin and agitated for 10 minutes at RT. Then the solution was drained and the resin washed with DMF (2 mL x 3). The acetylation was then repeated one more time. Resin Cleavage The resin was shrunk using washes of DCM (3 x 1 mL) and then diethyl ether (3 x 1 mL). The resin was then treated with a cleavage cocktail (3 mL) containing 94:2.5:2.5:1 TFA : H2O : EDT : TIPS for 4 hours at rt. The resulting solution was filtered from the resin into 25 mL diethyl ether and stored over night at -20 °C to precipitate out. The precipitate was separated by centrifugation and the aqueous layer decanted, another portion of diethyl ether (25 mL) was added and the separation repeated. The resulting peptide was dissolved in 10 mL MeCN/H2O (1:1) and lyophilized. Where necessary, a test cleavage was carried out by using 200 μL of the cleavage cocktail prepared for the full cleave, and combined with approx 1 mg of resin in a 1 mL eppendourf and left at RT for 45 minutes.20 μL of the supernatant was then combined with 200 μL 1:1 H2O/MeCN and analysed by LC-MS. HPLC Purification Purification of peptides and peptide-peptoid hybrids was conducted using an Interchim Puriflash 450 system with a sunfire C18 column (19 x 100 mm). Samples were injected into the column and ran in a gradient of 5-95% solvent B, where solvent B was MeCN and solvent A was 0.01% formic acid in H2O. The gradient used was either according to method 1 or 2, both with a flow rate of 17.0 ml/min and the absorbance measured at 220 nm. Method 1: 95-65% A over 16 minutes followed by 65-5% A over 2 minutes and then held at 5% A for 2 minutes. Method 2: 95-75% A over 6 minutes followed by 75-5% A over 2 minutes A and then held at 5% A for 2 minutes. Fractions were collected and analysed by LCMS. The fractions containing the desired product were combined and lyophilised. HPLC Analysis Samples were dissolved in 1:1 H2O/MeCN and 75 μL was injected into a Perkin Elmer Series 200 LC Pump, with a Series 200 UV/Vis detector attached to a XBridge BEH C18 column (25 cm x 4.6 mm). A gradient of 0-100% solvent B was used. Where solvent B was 95% MeCN, 5% H2O and 0.03% TFA and solvent A was 95% H2O, 5% MeCN and 0.05% TFA. The gradient was over 40 minutes with a flow rate of 1.0 ml/min. Absorbance was measured at 220 nm and processed by TotalChem software. Tissue Culture Experiments Optical imaging methods, consisting of voltage-sensitive dye imaging (VSDI) were performed in house on coronal p21 rat slices in basal forebrain. T30 and 613 variants were used at 2 and 4 µM, respectively. Animals Male Wistar rats (Charles River, United Kingdom) of age postnatal day 21 (P21) were used for optical imaging experiments. All animal procedures are approved by the Home Office UK (according to “Schedule 1” regulations) and conducted in compliance with the requirements of the UK Animals (Scientific Procedures) Act 1986. Brain slice preparation Preparation of the sections was carried out as previously described (Badin AS, Morrill P, Devonshire IM, Greenfield SA. (2016) (II) “Physiological profiling of an endogenous peptide in the basal forebrain: Age-related bioactivity and blockade with a novel modulator.” Neuropharmacology, 105:47-60). In summary, after decapitating the animal, the brain was removed and placed in ice cold solution bubbled with carbogen (95% O2, 5% CO2) and containing (in mmol: 120 NaCl, 5 KCl, 20 NaHCO3, 2.4 CaCl2, 2 MgSO4, 1.2 KH2PO4, 10 glucose, 6.7 HEPES salt and 3.3 HEPES acid; pH: 7.1). Three consecutive 400 µm thick rat brain slices containing the basal forebrain (1.20 to 0.00 mm from Bregma) were sectioned using a Leica VT1000S vibratome. The sections comprised different areas including: the medial septum (MS), the vertical diagonal band (VDB) and the horizontal diagonal band (HDB), the substantia innominata (SI) including the nucleus basalis of Meynert (NBM). Consecutively, each slice was cut along the midline in two hemisections which were transferred to a bubbler pot with artificial cerebro-spinal fluid (aCSF) (‘recording’ aCSF in mmol: 124 NaCl, 3.7 KCl, 26 NaHCO3, 2 CaCl2, 1.3 MgSO4, 1.3 KH2PO4 and 10 glucose; pH: 7.1) and incubated at 34°C for 20 minutes (min). The hemisections were kept at room temperature (RT) for 30 min in oxygenated (95% O2, 5% CO2) aCSF to recuperate before VSD staining. Optical and electrophysiology field recording method Each electrophysiology and VSDI experiment was performed as formerly described (Badin et al., 2016). Briefly, excitatory postsynaptic potential (fEPSP) recordings and optical imaging using a voltage-sensitive dye, Di-4-ANEPPS (4% 0.2 mM styryl dye pyridinium 4-[2-[6-(dibutylamino)-2-aphthalenyl]-ethenyl]-1-(3-sulfopropyl) hydroxide; Sigma-Aldrich, D8064, Germany), dissolved in aCSF (artificial cerebro- spinal fluid), fetal bovine serum 48%, DMSO 3.5% and cremophore EL 0.4%), were subsequently carried out after a 20 min incubation with the dye. Sections were then transferred and kept in aCSF (at room temperature, 22°C ± 1.5°C) for 45 minutes to wash off the dye excess and favour the recovery phase. The dye was chosen because it is characterised by minimal pharmacological side effects or phototoxicity and a high signal-to-noise ratio (Grandy, T.H.; Greenfield, S.A.; Devonshire, I.M. An evaluation of in vivo voltage-sensitive dyes: Pharmacological side effects and signal-to-noise ratios after effective removal of brain-pulsation artifacts. J. Neurophysiol.2012, 108, 2931– 2945). After incubation with the dye, for each imaging session, hemisections were placed in the recording bath, continuously perfused with oxygenated aCSF (in mmol: 124 NaCl, 3.7 KCl, 26 NaHCO3, 2 CaCl2, 1.3 MgSO4, 1.3 KH2PO4 and 10 glucose; pH: 7.1) and warmed to 30°C ± 1°C with a temperature control system (TC-202A, Digitimer Research Instruments, Hertfordshire, UK). Slices were kept in position with a home- made plastic grid before placing the stimulating electrode (Pt-Ir concentric bipolar FHC electrodes, Bowdoin, USA; outer pole diameter 200 μm, inner pole diameter 25 μm) and the recording electrode in an area of the BF comprised between the HDB and VDB. Each experimental session consisted of a 25-minute perfusion epoch per different treatment, subdivided in a 15 min recording period preceded by a 10 min slice acclimatisation to the recording bath. Data analysis Each electrophysiology and VSDI experiment was analysed as previously described (Badin et al., 2016). In short, VSDI data were recorded in 4 x 4 mm 2-dimensional images, equivalent to 100 x 100 pixels (each pixel measuring 40 x 40 micrometres), from which information was extracted. The duration of VSDI recordings was approximately 15 min long per condition with an ISI between stimulations equivalent to that used for electrophysiology (28 s). Optical imaging data were processed using a toolbox implemented in MatLab (The Mathworks Inc, USA) (Bourgeois, E.B.; Johnson, B.N.; McCoy, A.J.; Trippa, L.; Cohen, A.S.; Marsh, E.D. A toolbox for spatiotemporal analysis of voltage-sensitive dye imaging data in brain slices. PLoS ONE 2014, 9). The region of interest was post-hoc visually drawn onto the slice to comprehend the global evoked VSDI responses of the BF area. VSDI data refer to results from the selected ROI plotted as the magnitude of BF activity over space and time (‘space-time’ maps), as summed fluorescence fractional change indicated by the value calculated from the area under the curve between 0 and 300 milliseconds (ms) after stimulation delivery (ƩΔF/F0), or as averaged summed activity. The colour map employs warm and cool colours representing depolarization or no response. Statistical analysis All statistical analyses were performed using GraphPad Prism 6 (v6.05; GraphPad Software Inc., CA, USA) and, as all the data were tested for normality, only parametric tests (unpaired t tests, one-way Analysis of Variance (ANOVA) followed by Fisher LSD post hoc tests or by Tukey’s post hoc test when groups number was > 3) were used. For all statistical tests, p < 0.05 was considered significant; data are expressed as mean ± SEM (standard error of the mean). Statistical significance: *p < 0.05; **p < 0.01, ***p < 0.001, ns = non-significant. Cell Culture Experiments PC12 cell cultures PC12 cells are a cloned, pheochromocytoma cell line derived from the adrenal medulla (Greene and Tischler, 1976, Proc Natl Acad Sci U S A 73: 2424-2428; Mizrachi et al., 1990, Proc Natl Acad Sci U S A 87: 6161-6165). They are easily cultured and readily accessible to experimental manipulations. Since chromaffin cells are derived from the neural crest but are located in the centre of an accessible peripheral organ (the adrenal medulla) they have been described as offering a ‘window’ into the brain (Bornstein et al., 2012, Mol Psychiatry 17: 354-358). These cells serve as a powerful, albeit novel, in vitro model for studying the still unknown primary process of neurodegeneration and the reasons why they are useful for this project are the following: the adrenal medulla in Alzheimer's patients shows various pathological features reminiscent of those seen in the CNS, e.g. numerous Lewy-body like inclusions, neurofibrillary tangles and paired helical filaments, as well as expression of amyloid precursor protein (APP) (Takeda et al., 1994, Neurosci Lett 168: 57-60). Moreover Appleyard and Macdonald (1991, Lancet 338: 1085-1086) demonstrated a selective reduction only in the soluble (i.e. releasable) form of AChE from the adrenal gland in AD, perhaps due to its enhanced secretion into the plasma, where it is elevated in AD patients (Atack et al., 1985, J Neurol Sci 70: 1-12; Berson et al., 2008, Brain 131: 109-119). Wild-type PC12 cells were provided by Sigma-Aldrich (St. Louis, MO). The PC12 cell culture or preparation was routinely plated in 100 mm dishes (Corning) coated with collagen (2μg/cm2) and maintained in growth medium with Minimum Essential Medium Eagle (MEM) supplemented with heat-inactivated 10% horse serum (HS) and 5% foetal bovine serum (FBS), 10 mM HEPES, 2mM L-Glutamine and 1:400 Penicillin/ streptomycin solution. Cells were maintained at 37 °C in a humidified atmosphere 5% CO2 and the medium was replaced every 2 days. For splitting, cells were dislodged from the dish using a pipette with medium, with a portion of these replated onto new cultured dishes. Cells were used between passages 12 and 25. Calcium fluorometry PC12 cells were plated in 100 uL of full DMEM 2 days before the experiment was conducted in a 96 well microplate. Fluo-8 solution was prepared as described by the manufacturer (Abcam, 112128). Briefly, 1 mL of Pluronic F127 Plus was added to 9 mL Hank’s Balanced Salt Solution (HBSS). To this, 10 uL of Fluo-8 dye (reconstituted in DMSO) was added to prepare the full fluo-8 solution for the assay.100 uL of the media was removed from each well, and the cells were treated with T14, or T14 with/or antagonist at different concentrations as appropriate (70 uL of Fluo-8 solution with T14/T14 + NBP was added to each well). Since we have previously shown that T14 was most potent when used at concentration 250 nM (4), therefore the two peptides were tested against T14 at 250 nM for all assays across all doses. The plate was then incubated in the incubator at 37 °C for 30 minutes, and then at room temperature for 2 hours in total darkness. After the dark incubation, the plate was placed in a fluorescence plate reader (Fluostar, Optima, BMG Labtech, Ortenberg, Germany). Before the fluorescence was read, acetylcholine (128 μM), an agonist of nicotinic receptors was prepared and placed in the Fluostar injector. For each well, the reading was determined by a basal fluorescence reading, following by an acetylcholine injection (50 uL) that induced an increase in calcium influx via nicotinic receptors, at a final concentration of 53.3 μM. The Ex/Em fluorescence intensity was measured at 490/525 nm. For data-analysis, the basal fluorescence reading was subtracted from the max reading, and each value was represented as a percentage of their respective control to control for inter-assay variability. Each plate provided 6 technical replicates for a particular condition, which was averaged to give one mean value per condition per plate. Acetylcholinesterase activity assay AChE activity was measured using the MAK119 AChE assay kit from Sigma-Aldrich (St Louis, MO), which is based on the Ellman assay. Thiocholine is produced by AChE and reacts with 2-nitrobenzoic acid, forming a yellow-coloured product which is directly proportional to the activity of AChE. PC12 cells were plated in a 96 well microplate in 100 uL of full DMEM 2 days before the experiment was conducted. On the day of the experiment, treatment with T14 or T14 + antagonist was prepared in HHBS (HBSS supplemented with HEPES).100 uL of media was removed from each well, and the cells were then treated with 30 uL of HHBS with T14/T14 + NBP at appropriate concentrations. After an average of 3.5 hours of incubation in the incubator at 37 °C, the supernatant was removed from each well. Supernatants from two wells with the same condition were combined, which was dispensed into a 96 well microplate. To each well, assay reagent dissolved in assay buffer (at 7.7:1 ratio) was added. The plate was then incubated for two minutes at room temperature, following which the absorbance was read at 405 nm in a Vmax plate reader (Molecular devices, Wokingham, UK) for 60 minutes, at an interval of 2 minutes each. For data-analysis, the activity of AChE was measured by subtracting the initial absorbance from the final absorbance, and each well was represented as a percentage of their respective control to remover inter-assay variability. Each plate provided 3 technical replicates, which were averaged to give one mean value per condition. Cell viability assay Cell viability was determined using the cell counting kit – 8 (CCK-8) purchased from Sigma (Merck, kGaA, Darmstadt, Germany, 96992). By utilising the water-soluble tetrazolium salt WST-8, CCK-8 reagent produces a water-soluble dye (formazan) upon being reduced in the presence of an electron carrier. WST-8 is reduced by dehydrogenases in cells to produce a yellow-coloured formazan dye, which is soluble in full tissue culture medium. The amount of formazan dye produced by the activity of dehydrogenases is directly proportional to the total number of living cells. PC12 cells were plated onto a 96 well microplate in 100 uL of full DMEM one day before the experiment was conducted. Treatment with T14 or T14 and/or antagonist were prepared in full DMEM, and 20 uL of treatment was added to each well with appropriate concentrations. The plate was then incubated at 37 °C for 4 hours, after which 12 uL of cck-8 dye (10% of total volume) was added to each well. The plate was then incubated at 37 °C for another hour before the absorbance was detected at 450 nm in a Vmax plate reader (Molecular Devices, Wokingham, UK). For data analysis, each value was represented as a percentage of control to control for inter-assay variability. Each plate provided 6 technical replicates per condition, which was averaged to give one mean value. Data analysis In each of the different techniques, the statistics analysis was performed with the average of the percentage values of 12 or more experiments. Comparisons between multiple treatment groups and the same control were performed by one-way analysis of variance (ANOVA) and Tukey's post-hoc tests using GraphPAD Instat (GraphPAD software, San Diego, CA). These tests compare the means of every treatment to the means of every other treatment; that is, apply simultaneously to the set of all pairwise comparisons and identify where the difference between two means is greater than the standard error would be expected to allow. Statistical significance was taken at a P value < 0.05. Graphs were plotted using GraphPAD Prism 6 (GraphPAD software, San Diego, CA).

Claims

Claims 1. A peptide derivative of Formula (I):

wherein R¹ is H, a C_1-6 alkyl or COR⁹; one of R^2a and R^2b is H and the other is a C2-8 alkyl or -L¹X¹R¹⁰; one of R^3a and R^3b is H and the other is H or a C_1-6 alkyl; one of R^4a and R^4b is H and the other is H or is an optionally substituted C_1-6 alkyl, wherein the alkyl is unsubstituted or substituted with an optionally substituted 5 to 10 membered heteroaryl, an optionally substituted C_6-10 aryl, an optionally substituted 3 to 10 membered heterocycle or an optionally substituted C_3-10 cycloalkyl; one of R^5a and R^5b is H and the other is

one of R^6a and R^6b is H and the other is H or an optionally substituted C_1-8 alkyl, wherein the alkyl is unsubstituted or substituted with NH₂ or ;

one of R^7a and R^7b is H and the other is H or a C_1-6 alkyl; R⁸ is OH or NH₂; R⁹ is a C_1-6 alkyl; L¹ is a C_1-6 alkylene or is absent; X¹ is -S-, -O- or NH; R¹⁰ is H or is a C_1-6 alkyl; R¹¹ is a halogen, OR¹², NR¹²R¹³, SR¹², CN, NO₂, an optionally substituted C_1-6 alkyl, an optionally substituted C_6-10 aryl, an optionally substituted C_3-10 cycloalkyl, an optionally substituted 3 to 10 membered heterocycle or an optionally substituted 5 to 10 membered heteroaryl; R¹² and R¹³ are each independently H, an optionally substituted C_1-6 alkyl, an optionally substituted C_6-10 aryl, an optionally substituted C_3-10 cycloalkyl, an optionally substituted 3 to 10 membered heterocycle or an optionally substituted 5 to 10 membered heteroaryl; m is 0 or an integer between 1 and 6; and n is 0 or an integer between 1 and 4; or a pharmaceutically acceptable salt, solvate, complex, tautomer or polymorphic form thereof; with the proviso that the peptide derivative of Formula (I) is not:

2. The peptide derivative of claim 1, wherein the peptide derivative of Formula (I) is a compound of Formula (Ia):

3. The peptide derivative of claim 1 or claim 2, wherein R¹ is COR⁹ and R⁹ is a C_1-3 alkyl and is preferably methyl.

4. The peptide derivative of any preceding claim, wherein one or R^2a and R^2b is H and the other is n-propyl, n-butyl, n-pentyl, n-hexyl or is -L¹X¹R¹⁰, wherein L¹ is a C_1-6 alkylene, X¹ is S and R¹⁰ is a C_1-6 alkyl.

5. The peptide derivative of claim 4, wherein R^2a is H and R^2b is -CH₂CH₂SCH₃.

6. The peptide derivative of any preceding claim, wherein one or R^3a and R^3b is H and the other is a C_1-6 alkyl.

7. The peptide derivative of any preceding claim, wherein one of R^4a and R^4b is H and the other is an optionally substituted C_1-6 alkyl, wherein the alkyl is unsubstituted or substituted with an optionally substituted 5 or 6 membered heteroaryl, an optionally substituted phenyl, an optionally substituted 5 or 6 membered heterocycle or an optionally substituted C5-6 cycloalkyl.

8. The peptide derivative of any preceding claim, wherein one of R^5a and R^5b is H and the other is

or

9. The peptide derivative of any preceding claim, wherein one of R^6a and R^6b is H and the other is an optionally substituted C_1-8 alkyl, wherein the alkyl is unsubstituted or substituted with NH₂ or

10. The peptide derivative of any preceding claim, wherein one of R^7a and R^7b is H and the other is a C_1-6 alkyl.

11. The peptide derivative of any preceding claim, wherein R⁸ is OH.

12. The peptide derivative of claim 1, wherein the peptide derivative of Formula (I) is a peptide derivative of Formula (101) to (117):

13. A pharmaceutical composition comprising the peptide derivative any preceding claim and a pharmaceutically acceptable carrier.

14. The peptide derivative according to any one of claims 1 to 12 or a pharmaceutical composition according to claim 13, for use in therapy or diagnosis.

15. The peptide derivative according to any one of claims 1 to 12 or a pharmaceutical composition according to claim 13, for use in treating, ameliorating or preventing a neurodegenerative disorder.

16. The peptide derivative or composition for use according to claim 15, wherein the neurodegenerative disorder which is treated is selected from a group consisting of Alzheimer's disease; Parkinson's disease; Huntington's disease; motor neurone disease; Spinocerebellar ataxia (SCA) type 1, type 2, and type 3; Amyotrophic Lateral Sclerosis (ALS); schizophrenia; Lewy-body dementia; and Frontotemporal Dementia.