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WO2025094152A1 - Ligands de mchr1 tep radiomarqués par 18f et 11c - Google Patents

Ligands de mchr1 tep radiomarqués par 18f et 11c Download PDF

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WO2025094152A1
WO2025094152A1 PCT/IB2024/060862 IB2024060862W WO2025094152A1 WO 2025094152 A1 WO2025094152 A1 WO 2025094152A1 IB 2024060862 W IB2024060862 W IB 2024060862W WO 2025094152 A1 WO2025094152 A1 WO 2025094152A1
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diazepino
tetrahydro
pyridin
methoxy
indol
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Imre Bata
Péter SPRÁNITZ
György István TÚRÓS
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Richter Gedeon Nyrt
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Richter Gedeon Nyrt
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/002—Heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/041—Heterocyclic compounds
    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K51/0468—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole

Definitions

  • the present invention relates to radiolabeled 2,3,4,5-tetrahydro-1H- [1,4]diazepino[1,7-a]indol-9-yl]pyridin-2(1H)-one derivatives of general formula (I) and/or salts thereof, which are useful for binding and imaging melanin-concentrating hormone receptor 1 (MCHR1) in a mammal’s brain. Also, the present invention relates to certain precursors of formula (II) to said radioligands, to processes for the preparation thereof, and to intermediates of said processes. THE BACKGROUND OF THE INVENTION Numerous medical diagnostic procedures utilize radiolabeled compounds.
  • PET positron emission tomography
  • tracers The labeled compounds are absorbed, distributed, metabolized, and eliminated in vivo the same way as the corresponding non- radioactive compounds.
  • Tracers can be radiolabeled with a radionuclide useful for PET imaging, such as 11 C, 13 N, 18 F, 64 Cu, 68 Ga, 82 Rb and 124 I.
  • the PET method detects malfunction on cellular level in the investigation of tissues and organs. PET has been used in clinical oncology (imaging the tumors and metastases), in identification of specific brain diseases and mapping brain and heart functions.
  • Carbon-11 (t1/2 20.3 min) is one of the most frequently used radioisotopes in PET because of its abundance in organic molecules and short half-life which allows for multiple tracer administration on the same day to the same mammal, i.e., human or animal subject and reduces the radiation burden on the patients. Radiolabeling target molecules with carbon-11 is more challenging due to the shorter half-life of carbon-11 that prohibits long-run synthesis, and multistep reactions. Some effective strategies must consider carbon-11 radiochemistry, which include the design of reaction method in a way that carbon-11 radionuclide should be introduced in the last step. The 11 C-tracer is then purified by HPLC, which significantly increases the loss of the tracer and production time, and complicates automation.
  • the melanin-concentrating hormone is a cyclic polypeptide consisting of 19 amino acids, produced predominantly by neurons in the lateral hypothalamus, incerto- hypothalamic area with extensive projections throughout the brain (Bittencourt, Gen Comp Endocrinol 2011, 172:185–97.
  • MCH receptor 1 (Saito et al., Nature 1999, 400:265–69, Shimomura et al., Biochem Biophys Res Commun 1999, 261:622–26) and MCH receptor 2 (MCHR2) (Sailer et al., Proc Natl Acad Sci USA 2001, 98:7564–69). Since only the MCHR1 is functional in rodents, the physiological importance of MCHR2 remains unknown due to the lack of appropriate animal models.
  • GPCRs GPCRs
  • MCH signaling is also involved in a variety of psychiatric disorders, such as depression and anxiety (Smith et al., Neuropsychopharmacology 2006, 31:1135–45).
  • MCH fibers could control the activity of ciliated cells to initiate an increase in CSF flow to meet metabolic needs. This strongly supports the idea that the MCH-system may also be involved in non-neuronal intercellular communication, but evidence is still lacking.
  • Antagonism of MCHR1 is one of the viable targets for obesity therapy (Pissios, Peptides 2009, 30:2040-44).
  • MCH is the only known peptide whose ablation results in leanness (Rivera et al., Curr Med Chem 2008, 15:1025-43).
  • a suitable PET tracer needs to be developed.
  • SNAP-7941 is a potent MCHR1 antagonist, which contains a methyl ester ( Figure 1, Compound A), making the molecule suitable for introducing either a [ 11 C]methyl moiety or a [ 18 F]fluoroethyl moiety (Borowsky et al. Nat Med 2002, 8:825–30).
  • Potential PET tracers for the visualization of the MCHR1 were developed such as [ 11 C]SNAP-7941 ( Figure 1, Compound B) and [ 18 F]FE@SNAP ( Figure 1, Compound C).
  • CSA cyclosporine A
  • Diazepino-indole derivatives have selective antagonistic effect on the MCHR1 receptors that is known in the art (WO 2016/166684 A1) but structurally close radiolabeled MCHR1 PET ligands have not been synthesized so far.
  • MCHR1 PET radioligands have been developed but none of them was shown to be suitable for clinical research so far. Accordingly, there is an unmet need to provide MCHR1 PET radioligands that can be useful in human clinical research.
  • the present invention relates to a radiolabeled compound of general formula (I) or a pharmaceutically acceptable salt thereof.
  • the present invention also relates to a precursor compound of general formula (II) or a salt thereof.
  • the present invention also relates to a precursor compound of general formula (III) or a salt thereof.
  • the present invention relates to a process for the preparation of a radiolabeled compound of general formula (I) or a pharmaceutically acceptable salt thereof.
  • the present invention also relates to a process for the preparation of a precursor compound of general formula (II) or a pharmaceutically acceptable salt thereof.
  • the present invention relates to a radiolabeled compound of general formula (I) or a pharmaceutically acceptable salt thereof for use as PET tracers.
  • BRIEF DESCRIPTION OF THE FIGURES Figure 1: Structures of MCHR1 PET ligands known in the art.
  • Figure 2 In vivo dynamic PET imaging of the brain uptake of healthy control Wistar rats after intravenous injection of Example 8.
  • FIG. 1 Representative decay-corrected dynamic PET images ( Figure 2A) and SUVmean time-activity curve (TAC) ( Figure 2B) of Example 8 in the brain of healthy Wistar rats. Black circles: brain area.
  • Figure 3 In vivo dynamic PET imaging of the brain uptake of healthy control Wistar rats after intravenous injection of Example 9.
  • Figure 4 In vivo dynamic PET imaging of the brain uptake of healthy control Wistar rats after intravenous injection of Example 10.
  • FIG. 4A Representative decay-corrected dynamic PET images ( Figure 4A) and SUVmean time-activity curve (TAC) ( Figure 4B) of Example 10 in the brain of healthy Wistar rats. Black circles: brain area.
  • Figure 5 In vivo PET imaging of the brain uptake of healthy control Wistar rats after intravenous injection of Reference Example 3 alone and after CSA pretreatment. Representative decay-corrected summa PET images (0 – 180 min, Figure 5A) and SUVmean time-activity curve (TAC) ( Figure 5B). Black circles are the brain area.
  • Figure 6 In vivo PET imaging of the brain uptake of healthy control Wistar rats after intravenous injection of Example 11 alone and after CSA pretreatment.
  • FIG. 8 Representative decay- corrected static PET images (0 – 40 min, Figure 6A) and SUVmean time-activity curve (TAC) ( Figure 6B). Black circles and arrows are brain area.
  • Figure 7 Ex vivo biodistribution 30 and 180 min after the intravenous injection of Example 8 in healthy control Wistar rats.
  • Figure 8 PET/MRI summation images between 40-60 min ( Figure 8A) and PET/CT summation images between 80-100 min ( Figure 8B) in the cynomolgus monkey brain after receiving a single i.v. injection of Example 8. Black circles indicate the higher PET concentrations.
  • Figure 9 Regional TAC recorded from the brain of cynomolgus monkey.
  • the present invention relates to a radiolabeled compound of general formula (I): wherein A is CH or N; R 1 is 18 F and R 2 is CH 3 , or CH(CH 3 ) 2 group, or R 1 is F and R 2 is 11 CH 3 group, or a pharmaceutically acceptable salt thereof.
  • the compound of general formula (I) is a compound wherein A is CH or N, R 1 is 18 F, R 2 is CH 3 , or CH(CH 3 ) 2 group, or a pharmaceutically acceptable salt thereof.
  • the compound of general formula (I) is a compound wherein A is CH , R 1 is 18 F, R 2 is CH 3 , or CH(CH 3 ) 2 group, or a pharmaceutically acceptable salt thereof.
  • the compound of general formula (I) is a compound wherein A is CH or N, R 1 is F, R 2 is 11 CH3, or a pharmaceutically acceptable salt thereof.
  • the compound of general formula (I) is a compound wherein A is CH, R 1 is F, R 2 is 11 CH 3 , or a pharmaceutically acceptable salt thereof.
  • the radiolabeled compound of general formula (I) is selected from the group consisting of: 4- ⁇ [4-( 18 F)fluorophenyl]methoxy ⁇ -1-[3-(propan-2-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino [1,7-a]indol-9-yl]pyridin-2(1H)-one, 4- ⁇ [4-( 18 F)fluorophenyl]methoxy ⁇ -1-(3-methyl-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a] indol-9-yl)pyridin-2(1H)-one, 4-[(4-Fluorophenyl)methoxy]-1-[3-( 11 C)methyl-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a] indol-9-yl]pyridin-2(1H)-one
  • the present invention also relates to a fluorine-18 precursor compound of general formula (II): wherein R 1 is B(O-C(R 3 ) 2 -C(R 3 ) 2 -O) group; R 2 is CH 3 , CH(CH 3 ) 2 , or COOC(CH 3 ) 3 group; R 3 is CH3 or C2H5 group, or a salt thereof.
  • the compound of the general formula (II) is selected from the group consisting of: 1-[3-(Propan-2-yl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indol-9-yl]-4- ⁇ [4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methoxy ⁇ pyridin-2(1H)-one, 1-(3-Methyl-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indol-9-yl)-4- ⁇ [4-(4,4,5,5- tetraethyl-1,3,2-dioxaborolan-2-yl)phenyl]methoxy ⁇ pyridin-2(1H)-one, 4- ⁇ [4-(4,4,5,5-Tetraethyl-1,3,2-dioxaborolan
  • the present invention also relates to a carbon-11 precursor compound of general formula (III): wherein A is CH or N, or a pharmaceutically acceptable salt thereof.
  • the compound of the general formula (III) is selected from the group consisting of: 4-[(4-fluorophenyl)methoxy]-1-(2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indol-9- yl)pyridin-2(1H)-one maleate salt, and 4-[(5-fluoropyridin-2-yl)methoxy]-1-(2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7- a]indol-9-yl)pyridin-2(1H)-one maleate salt.
  • the present invention relates to a radiolabeled compound of general formula (I) or a pharmaceutically acceptable salt thereof for use as PET tracers.
  • the present invention also relates to a radiolabeled compound of general formula (I) or a pharmaceutically acceptable salts thereof for use in visualizing localization or distribution of MCHR1 receptors in mammals by means of PET imaging, including rodents, NHPs and humans.
  • the term ‘mammal’ refers to any vertebrate animal of the class Mammalia, including, but not limited to, guinea pig, any rodent (such as hamster, mouse, rat), any non-human primate (such as cynomolgus macaque, rhesus macaque, baboon, marmoset, and green monkey) or human subject.
  • the present invention also relates to a process for the preparation of a compound of general formula (I).
  • the present invention also relates to a process for the preparation of a compound of general formula (II). Accordingly, a compound of general formula (I) or a compound of general formula (II) can be prepared by one of the following methods.
  • a compound of general formula (II) can be synthesized by one of the following methods (Reaction Scheme 3): Reaction Scheme 3
  • the compound of formula (3) was obtained from compound of formula (1) [Reference Example 1 of WO2016/166684] by reacting the compound of formula (2) [Example 1, step (2) in EP1741703] in step (i): in the presence of a catalyst, preferably copper(I) iodide, a base, preferably Cs 2 CO 3 , a ligand, preferably trans-N,N’-dimethylcyclohexan-1,2-diamine, under heated reaction conditions, preferably at 110 o C, in an inert solvent, preferably in toluene under Ar.
  • a catalyst preferably copper(I) iodide
  • a base preferably Cs 2 CO 3
  • a ligand preferably trans-N,N’-dimethylcyclohexan-1,2-diamine
  • the intermediate of formula (4) was prepared from compound of formula (3) via step (ii) in a debenzylation step, preferably in the presence of a hydrogen gas, a catalyst, preferably Pd/C, under acidic conditions, preferably AcOH in MeOH at RT.
  • the compound of formula (6) was synthesized from compound of formula (4) with a suitable benzyl bromide derivative (compound of formula 5) in the following step (iii): in the presence a base, preferably NaH, under normal reaction conditions, preferably at RT, in an inert solvent, preferably in DMF under Ar.
  • the compound of formula (7) was prepared from the compound of formula (6) via step (iv) in a deprotection step, preferably using HCl in EtOAc at RT.
  • a precursor compound of general formula (II) was obtained from the compound of formula (7).
  • R 2 is CH 3 group in a compound of general formula (II)
  • aqueous formaldehyde solution was used with NaBH(OAc)3 in a mixture of MeOH and DCM solvent in step (v).
  • R 2 is CH(CH3)2 group in a compound of general formula (II)
  • an alkylating agent preferably 2- iodopropane, a base, preferably K 2 CO 3 , under heated reaction condition, preferably at 80 o C, in a bipolar aprotic solvent, preferably in CH3CN (step (vi)).
  • a precursor compound of general formula (II) was obtained from the compound of formula (11) according to step (iii).
  • the compound of formula (11) was prepared from compound of formula (10) via debenzylation step according to step (ii).
  • the compound of formula (10) was obtained from compound of formula (9) reacting compound of formula (2) via step (i).
  • the compound of formula (9) was obtained from compound of formula (8) according to step (v) or (vi).
  • the compound of formula (8) was prepared from compound of formula (1) in a deprotection step according to step (iv).
  • Reference Example 1 was originally synthesized by carrying out a Mitsunobu synthesis with a 4-hydroxy-pyridinone intermediate (12) and a 4-fluoro-benzylalcohole (13) (Haga et al., Bioorg Med Chem 2011, 19:883-93; Reaction Scheme 4).
  • 1 2 13 Reference example 1 TC ⁇ MCH 7c Reaction Scheme 4
  • the key intermediate was a 4-bromo-pyridinone derivative (14).
  • Fluorine-18 was recovered from the anion exchange column by elution with a solution containing 805 mL of stock solution (which was prepared from 2.3 mg/mL K222 in MeCN) and 240 mL of aqueous solution (made from 9 mg of K2CO3 and 12 mg of KOTf in 10 mL ultrapure water). The eluate was dried between 85 and 125 o C in a nitrogen stream with vacuum.
  • radioactive solution For shaping of the radiolabeled product, 4 mL of the radioactive solution was filtered through a Millex sterile filter (0.22 ⁇ m x 4mm), diluted 10 mL of PBS, adjusted the pH 6.5 with 1.6 mL of 1N NaOH solution, and ensured the resistance of the preparation to radiolysis with 1.5 mL 10% of sodium ascorbate solution.
  • Example 1 4-[(4-fluorophenyl)methoxy]-1-[3-(propan-2-yl)-2,3,4,5-tetrahydro-1H- [1,4]diazepino[1,7-a] indol-9- 2(1H)-one The title compound and its synthesis were described in Example 21 of WO2016/166684. MS (ESI): 446.2 [M+H] + .
  • Example 2 4-[(4-Fluorophenyl)methoxy]-1-(3-methyl-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7- a]indol-9-yl)pyridin-2(1H)-one a.) 9-bromo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indole hydrochloride To a solution of 5.35 g (14.7 mmol) of tert-butyl 9-bromo-1,2,4,5-tetrahydro-3H- [1,4]diazepino[1,7-a]indole-3-carboxylate [Reference Example 1 of WO2016/166684] in 73 mL of EtOAc, 50 mL of 20% HCl in EtOAc was added.
  • the suspension was cooled to 0 °C and 11.5 g (54.2 mmol) of NaBH(OAc)3 was added in one portion.
  • the cooling bath was removed, and the reaction mixture was allowed to heat to RT.
  • 10 mL of water was added, and the organic solvents were evaporated.
  • 100 mL of DCM was added, and the mixture was basified with saturated Na2CO3 solution.
  • Example 3 4-[(5-fluoropyridin-2-yl)methoxy]-1-(3-methyl-2,3,4,5-tetrahydro-1H- [1,4]diazepino[1,7-a]indol-9-yl)pyridin-2(1H)-one maleic acid salt
  • the synthesis and analytical characterization of the title compound were described in Example 9 of WO2016/166684.
  • Example 5 1-(3-methyl-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indol-9-yl)-4- ⁇ [4-(4,4,5,5- tetraethyl-1,3,2-dioxaborolan-2-yl)phenyl]methoxy ⁇ pyridin-2(1H)-one a.) tert-butyl 9-(4-hydroxy-2-oxopyridin-1(2H)-yl)-1,2,4,5-tetrahydro-3H-[1,4]diazepino [1,7-a]indole-3-carboxylate In a 3-necked 100 ml flask, 960 mg (1.98 mmol) of tert-butyl 9-[4-(benzyloxy)-2- oxopyridin-1(2H)-yl]-1,2,4,5-tetrahydro-3H-[1,4]dia
  • Example 7 4-[(5-fluoropyridin-2-yl)methoxy]-1-(2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indol- 9-yl)pyridin-2(1H)-one maleate salt
  • step (a) of WO2016/166684] was dissolved in the mixture of 15 mL DCM and 3 mL of MeOH.
  • Radiosynthesis Example 8 4- ⁇ [4-( 18 F)fluorophenyl]methoxy ⁇ -1-[3-(propan-2-yl)-2,3,4,5-tetrahydro-1H- [1,4]diazepino[1,7-a]indol-9-yl]pyridin-2(1H)-one According to the described method in Reference Example 3, the title compound was synthesized.
  • 10 mL of the radioactive solution was filtered through a Millex sterile filter (0.22 mm x 4mm), diluted 6.5 mL of PBS, adjusted the pH 6.5 with 0.8 mL of 1N NaOH solution, and ensured the resistance of the preparation to radiolysis with 0.91 mL of sodium ascorbate (1:10).
  • Example 9 4- ⁇ [4-( 18 F)fluorophenyl]methoxy ⁇ -1-(3-methyl-2,3,4,5-tetrahydro-1H-[1,4]diazepino [1,7-a]indol-9-yl)pyridin-2(1H)-one
  • the title compound was prepared from 1-(3-methyl-2,3,4,5-tetrahydro-1H- [1,4]diazepino [1,7-a]indol-9-yl)-4- ⁇ [4-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)phenyl] methoxy ⁇ pyridin-2(1H)-one
  • Example 5 in a copper(II)-mediated radio-fluorination reaction by a slightly modified method described in Example 8: the reaction time was 20 min at 90 o C.
  • Example 10 4-[(4-fluorophenyl)methoxy]-1-[3-( 11 C)methyl-2,3,4,5-tetrahydro-1H- [1,4]diazepino[1,7-a]indol-9-yl]pyridin-2(1H)-one
  • [ 11 C]CO2 was produced in a Siemens Eclipse RD cyclotron, which was reduced to firstly [ 11 C]CH 4 , and further converted to [ 11 C]CH 3 OTf by using a commercial radiochemistry platform (ScanSys).
  • Example 11 4-[(5-fluoropyridin-2-yl)methoxy]-1-[3-( 11 C)methyl-2,3,4,5-tetrahydro-1H- [1,4]diazepino[1,7-a]indol-9-yl]pyridin-2(1H)-one
  • the title compound was prepared from 4-[(5-fluoropyridin-2-yl)methoxy]-1-(2,3,4,5- tetrahydro-1H-[1,4]diazepino[1,7-a]indol-9-yl)pyridin-2(1H)-one maleate salt [Example 7] according to detailed procedure in Example 10.
  • Receptor binding assays were performed in 10 concentrations, with two parallel samples in each concentration using an incubation buffer (25 mM HEPES, pH 7.4, 10 mM MgCl2, 1 mM EDTA, 0.2% BSA), cell membrane of CHO-K1 cells steadily expressing hMCHR1 receptor, 1% DMSO as vehicle and 0.05 nM [ 125 I] Tyr-S36057 - as radioligand. Non-specific binding was determined in the presence of 1 ⁇ M MCH. Samples were incubated for 120 min at 25 °C. Binding reactions were terminated by rapid filtration and radioactivity was determined. Historical KD and historical B max of the optimized saturation binding was 0.1 nM and 26.0 pmole/mg protein, respectively.
  • Radioligand displacement by the test compounds were characterized by IC 50 values which were determined by a non-linear, least squares regression analysis using MathIQTM (ID Business Solutions Ltd., UK). Inhibition constants (Ki) are presented, the Ki values were calculated using the equation of Cheng and Prusoff (Cheng, Y., Prusoff, W. H., Biochem. Pharmacol. 1973, 22:3099-3108,) using the observed IC 50 of the tested compound, the concentration of radioligand employed in the assay, and the historical values for the KD (0.1 nM) of the radioligand (obtained experimentally at Eurofins Panlabs, Inc.). Hill coefficient (nH), defining the slope of the competitive binding curve, was calculated using MathIQ TM (version 1.0).
  • Example 1-3 exhibit a high binding affinity towards MCHR1.
  • the binding data of Reference Example 1 (TC-MCH 7c) was in good correlation with published data (Haga et al., Bioorg Med Chem 2011, 19:883-9)
  • Ex vivo MCHR1 receptor occupancy in rat striatal homogenate [ 3 H]SNAP binding
  • Male Wistar rats weighing 190-210 g were used. Rats were purchased from Toxi-Coop (Budapest, Hungary). Animals arrived at the facility at least four days before the experiment.
  • MCHR1 receptor occupancy was determined from 4 rats per dosing group. Decapitation and brain dissection took place 30 minutes after i.v. and 120 minutes after p.o. dosing and rat striatal tissue preparations were completed within a subsequent 5-minute time frame. Brain samples were rapidly frozen using dry ice and stored at -70 °C until use. Rat striatum was homogenized in 9 vol.
  • binding reactions were terminated by rapid filtration through a 96-well Filtermate Harvester (Perkin Elmer, Waltham, MA, USA) using UniFilter® GF/C (Perkin Elmer, Cat No.: 6055690) presoaked for at least 1 hour in 0.5% polyethylene imine (PEI, dissolved in distilled water).
  • PEI polyethylene imine
  • MCHR1 receptor occupancy was expressed as % inhibition of [ 3 H]SNAP-7941 binding relative to vehicle control. Data presentation: values are mean percentage of occupancy ⁇ SD.
  • Ex vivo occupancy data of the test compounds characterize the binding profile of Example 1-3 by showing that not only high percentages of MCHR1 receptor population are occupied but an improved level of occupancy is evidenced when compared to Reference Example 1. On the basis of these data, there was no correlation in binding data and ex vivo occupancy of Refence Example 1.
  • Table 1 In vitro human binding data and ex vivo occupancy in rat striatal homogenate Compound / PET ligand hMCHR1 Ex vivo occupancy (%) Ki (nM) rat, 1 mg/kg i.v.
  • Example 1/ Example 8 9 96.8+2.0
  • Example 2 / Example 9 and 10 13 77.5+5.3
  • Example 3 / Example 11 33 71.5+3.7 Reference Example 1/ Ref. Ex.3 5.6 39.6+5.4
  • the semi-synthetic diet (VRF1; Akronom Ltd., Budapest, Hungary) and drinking water were available ad libitum to all animals.
  • Example 8 After the qualitative analysis of the decay-corrected images were identified till 40 min after the intravenous (i.v.) administration of Example 8 ( Figure 2A). Analyzing the TAC data, continuous decreasing of the SUVmean values was observed in the brain ( Figure 2B). PET images show, that Example 8 was able to cross the blood-brain barrier, and the concentration of the radioactivity decreased with time. During the dynamic PET scans, the radioligand was very stable in rat plasma, there wouldn’t observed any radio-metabolites.
  • Example 9 and Example 10 Example 9 and Example 10, 11.07 ⁇ 2.9 MBq and 12.14 ⁇ 0.9 MBq in 150 ⁇ L saline injected respectively, were investigated via in vivo dynamic PET imaging according to the PET imaging method described with Example 8.
  • Example 11 was investigated according to the PET imaging method conducted with Reference Example 3. The compound entered in the brain after a CSA pretreatment on healthy Wistar rats. Representative decay-corrected static PET images of the brain (0 – 40 min) without CSA pretreatment ( Figure 6A, on the left) and with CSA pretreatment ( Figure 6A, on the right). Recycles and arrows: brain ( Figure 6A). Representative decay-corrected dynamic PET images and SUVmean time-activity curve (TAC) of Example 11 in the brain ( Figure 6B).
  • TAC time-activity curve
  • Example 8 radiotracer was expressed as %ID/g tissue.
  • Figure 7 shows the results of the biodistribution of Example 8. According to the data of imaging, the compound was excreted mainly through the liver of the investigated Wistar rats. In vivo PET imaging in non-human primates (NHP) All experimental procedures (except for housing and transportation) were conducted at the Medicopus facility in Kaposvár.
  • the animals were transported between their place of residence (GTRC, K ⁇ vágósz ⁇ l ⁇ s) and the neuroimaging site (Medicopus Ltd., Kaposvár) in a specially designed air- conditioned, and camera-equipped van (Dacia Dokker Van) in a special primate transport cage.
  • GTRC place of residence
  • Medicopus Ltd., Kaposvár neuroimaging site
  • Camera-equipped van Dacia Dokker Van
  • PRT positive reinforcement training
  • the transport cage can be attached to the housing cage, and the animals regularly visited it and receive their daily food in the transport cage). Thus, the transport to and from the measurement site was done with minimal stress effects on the animals.
  • animals were food and water deprived for 6 and 2 h respectively.
  • the anesthetic protocol was adapted to the individual sensitivity of the animals. The main objective was to ensure a steady deep anesthesia during the experiments, with adequate oxygen saturation and normal body temperature.
  • animals were first lightly anesthetized with a single dose of intramuscular (i.m.) ketamine injection (0.25 mg/kg, CP Ketamin, CP-Pharma, HU) and received a single dose of atropine injection i.m. (0.04-0.05 mg/kg, Atropinum Sulphuricum, Egis, HU) to prevent salivation.
  • animals received a mixture of 3.5-5% v/v isoflurane (Aerrane, Baxter, US) gas in 2 L/min flow of pure O2 through a face mask to induce deep aesthesia using a ventilation system in Mapleson-D arrangement.
  • an orally introduced supraglottic airway tube (laryngeal mask, Fazzini, IT) was inserted around the laryngeal inlet of the trachea and was sealed via a low-pressure cuff to secure the airway and stabilize ventilation.
  • a mixture of 1.5 V/V% isoflurane in 2 L/min pure O2 flow was used.
  • Example 8 The cynomolgus monkey (3.2 kg, female) received a single i.v. injection of Example 8 (140 MBq/3 mL). The PET measurement protocol was optimized explicitly for cynomolgus monkey.

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Abstract

La présente invention concerne des dérivés de 2,3,4,5-tétrahydro-1H-[1,4] diazépino [1,7-a] indol-9-yl] pyridin -2(1H)-one radiomarqués de formule générale (I) ou des sels de ceux-ci et des précurseurs de formules (II) et (III) desdits radioligands, leurs procédés de préparation et des intermédiaires desdits processus. Les composés radiomarqués permettent la visualisation et la quantification du récepteur 1 de l'hormone de concentration de mélanine (MCHR1) dans divers tissus cibles, y compris la surveillance du MCHR1 dans un tel tissu cible. Les composés présentent une affinité de liaison élevée vis-à-vis de MCHR1 et peuvent passer la barrière hémato-encéphalique, ce qui facilite le diagnostic d'une plage d'états pathologiques dans la recherche clinique humaine. (I)
PCT/IB2024/060862 2023-11-03 2024-11-04 Ligands de mchr1 tep radiomarqués par 18f et 11c Pending WO2025094152A1 (fr)

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HU2300374A HUP2300374A1 (hu) 2023-11-03 2023-11-03 18F és 11C radioaktívan jelzett MCHR1 PET ligandumok
HUP2300374 2023-11-03

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025218864A1 (fr) * 2024-04-18 2025-10-23 Helmholtz-Zentrum Dresden-Rossendorf E.V. Composés comprenant un motif 4,4,5,5-tetraalkyl-1,3,2-dioxaborolane

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005085200A1 (fr) 2004-03-05 2005-09-15 Banyu Pharmaceutical Co., Ltd. Dérivé pyridone
WO2007018248A1 (fr) 2005-08-10 2007-02-15 Banyu Pharmaceutical Co., Ltd. Composé de pyridone
US20120157460A1 (en) * 2010-12-21 2012-06-21 Albany Molecular Research, Inc. Tetrahydro-azacarboline mch-1 antagonists, methods of making, and uses thereof
WO2016166684A1 (fr) 2015-04-15 2016-10-20 Richter Gedeon Nyrt. Dérivés d'indole

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005085200A1 (fr) 2004-03-05 2005-09-15 Banyu Pharmaceutical Co., Ltd. Dérivé pyridone
EP1741703A1 (fr) 2004-03-05 2007-01-10 Banyu Pharmaceutical Co., Ltd. Derive pyridone
WO2007018248A1 (fr) 2005-08-10 2007-02-15 Banyu Pharmaceutical Co., Ltd. Composé de pyridone
US20120157460A1 (en) * 2010-12-21 2012-06-21 Albany Molecular Research, Inc. Tetrahydro-azacarboline mch-1 antagonists, methods of making, and uses thereof
WO2016166684A1 (fr) 2015-04-15 2016-10-20 Richter Gedeon Nyrt. Dérivés d'indole
EP3286193B1 (fr) * 2015-04-15 2020-05-27 Richter Gedeon Nyrt. Dérivés d'indole

Non-Patent Citations (22)

* Cited by examiner, † Cited by third party
Title
BITTENCOURT, GEN COMP ENDOCRINOL, vol. 172, 2011, pages 185 - 97
BOROWSKY ET AL., NAT MED, vol. 8, 2002, pages 825 - 30
CHENG, Y.PRUSOFF, W. H., BIOCHEM. PHARMACOL., vol. 22, 1973, pages 3099 - 3108
GARG ET AL., J. NUCL. MED., vol. 58, no. 3, 2017, pages 473 - 78
GUYON ET AL., J NEUROSCI, vol. 29, 2009, pages 2528 - 33
HAGA ET AL., BIOORG MED CHEM, vol. 19, 2011, pages 883 - 93
IGAWA ET AL., CURR RADIOPHARM, vol. 10, 2017, pages 35 - 40
LAJTOS ET AL., NUC. INT. METH. IN PHYS. RES. A, vol. 707, 2013, pages 26 - 34
MIKECZ ET AL., NUCL MED REV, vol. 20, no. 2, 2017, pages 111
PANFEN ET AL., DRUG MET. DISP., vol. 47, no. 11, 2019, pages 1352 - 60
PHILIPPE ET AL., MOL IMAG BIOL, vol. 21, 2019, pages 257 - 68
PHILIPPE ET AL., NUCL MED BIOL, vol. 40, 2013, pages 919 - 25
PHILIPPE ET AL., SCI PHARM, vol. 81, 2013, pages 625 - 39
PISSIOS, PEPTIDES, vol. 30, 2009, pages 2040 - 44
RIVERA ET AL., CURR MED CHEM, vol. 15, 2008, pages 1025 - 43
SAILER ET AL., PROC NATL ACAD SCI USA, vol. 98, 2001, pages 7564 - 69
SAITO ET AL., NATURE, vol. 400, 1999, pages 265 - 69
SHIMOMURA ET AL., BIOCHEM BIOPHYS RES COMMUN, vol. 261, 1999, pages 622 - 26
SMITH ET AL., NEUROPSYCHOPHARMACOLOGY, vol. 31, 2006, pages 1135 - 45
TREDWELL ET AL., ANGEW. CHEM. INT. ED., vol. 53, no. 30, 2014, pages 7751 - 55
YANG ET AL., INT. J. MOL. SCI., vol. 21, no. 19, 2020, pages 7023 - 50
ZIRSBERGER K ET AL., EJNMMI RADIOPHARM CHEM., vol. 2, no. 10, 2017, pages 1 - 12

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025218864A1 (fr) * 2024-04-18 2025-10-23 Helmholtz-Zentrum Dresden-Rossendorf E.V. Composés comprenant un motif 4,4,5,5-tetraalkyl-1,3,2-dioxaborolane

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