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WO2008133730A2 - Analogues de roténone marqués - Google Patents

Analogues de roténone marqués Download PDF

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Publication number
WO2008133730A2
WO2008133730A2 PCT/US2007/084870 US2007084870W WO2008133730A2 WO 2008133730 A2 WO2008133730 A2 WO 2008133730A2 US 2007084870 W US2007084870 W US 2007084870W WO 2008133730 A2 WO2008133730 A2 WO 2008133730A2
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Prior art keywords
rotenone
patient
region
analogs
imaging
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WO2008133730A3 (fr
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James P. O'neil
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University of California Berkeley
University of California San Diego UCSD
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University of California Berkeley
University of California San Diego UCSD
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
    • C07D493/14—Ortho-condensed systems
    • 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
    • A61K51/0412—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K51/0421—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom

Definitions

  • Coronary heart disease is the leading cause of death in the United States, accounting for roughly 24% of all deaths.
  • the cost of cardiovascular diseases in 1999 is estimated by the American Heart Association (AHA) at $286.5 billion.
  • Myocardial perfusion scintigraphy is widely used in the evaluation of patients with known or suspected coronary artery disease (CAD).
  • CAD coronary artery disease
  • the extensive clinical use of stress myocardial perfusion imaging has resulted largely from its demonstrated improved diagnostic sensitivity and specificity for detection of CAD as compared with exercise electrocardiogram.
  • myocardial flow tracers with improved tracer kinetics.
  • tracers Although several tracers are currently available for perfusion imaging, all of these tracers suffer from one or more limitations which render them less than ideal agents for assessment of cardiac perfusion (e.g., limited extraction at high flow (Tc99m-sestamibi, Tl-201 Chloride) (Marshall et al., 1990), lack of ideal isotope (Tl- 201 chloride), high liver extraction (Tc99m-teboroxime and Tc99m-sestamibi) (Marshall et al, 1991).
  • Tc99m-sestamibi Tl-201 Chloride
  • Tc99m- 201 chloride high liver extraction
  • Tc99m-teboroxime and Tc99m-sestamibi Marshall et al, 1991.
  • Myocardial perfusion tracers are needed with: improved extraction on first pass; better linearity with true blood flow; improved detection of myocardial viability; and reduced accumulation in non cardiac tissues.
  • radiopharmaceuticals may be used as diagnostic or therapeutic agents by virtue of the physical properties of their constituent radionuclides. Thus, their utility is not based on any pharmacologic action.
  • Most clinically used drugs of this class are diagnostic agents incorporating a gamma-emitting nuclide which, because of physical or metabolic properties of its coordinated ligands, localizes in a specific organ after intravenous injection. The resultant images can reflect organ structure or function.
  • the radiolabel is a gamma-radiation emitting radionuclide and the radiotracer is located using a gamma-radiation detecting camera (this process is often referred to as gamma scintigraphy).
  • the imaged site is detectable because the radiotracer is chosen either to localize at a pathological site (termed positive contrast) or, alternatively, the radiotracer is chosen specifically not to localize at such pathological sites (termed negative contrast).
  • radionuclides are known to be useful for radioimaging, including Ga- 67, Tc-99m, In-IU, 1-123, 1-125, Yb-169 and Re-186.
  • Rotenone, [2R,6aS, 12aS]- 1 ,2, 12, 12a-tetrahydro-8,9-dimethoxy-2-(l - methylethenyl)-[l]benzopyrano[3,4-b]furo[2,3-h]benzopyran-6(6aH)-one is a natural product of the Leguminosae plant family and has been used as an insecticide, pesticide and fish poison, and has been used in mitochondrial energy metabolism studies. Rotenone binds on the ND-I gene product and inhibits Complex I in a reversible competitive manner resulting in the biological effect.
  • Rotenone has a high affinity for mitochondria.
  • the myocardium is an organ rich in mitochondria. Novel radiolabeled rotenone analogs that display efficient myocardial uptake and adequate myocardial retention are attractive candidates for clinical evaluation of myocardial blood flow.
  • Rotenone is a specific, high-affinity inhibitor of Complex I (NADH ubiquinone oxidoreductase), the proximal enzyme of the mitochondrial electron transport chain. Since rotenone inhibition defines the activity of Complex I, defects in radiotracer binding can be expected to reflect functional changes in the enzyme, and hence, abnormalities of the mitochondrial energy metabolism.
  • Complex I NADH ubiquinone oxidoreductase
  • X is iodine, bromine, chlorine, or fluorine.
  • the iodine may be any iodine isotope including, for example, 1, 120 1, 121 1, 122 1, 123 1, 124 1, 125 1, 127 I, or 131 I.
  • the fluorine may be any fluorine isotope including, for example, F, 18 F, or 19 F.
  • the chlorine may be any chlorine isotope including, for example, Cl, 35 Cl, or 37 Cl.
  • the bromine may be any bromine isotope including, for example, Br, 75 Br, 76 Br, 77 Br, 79 Br, 80 Br, 80m Br, or 81 Br.
  • the fluorine may be a fluorine isotope
  • the fluorine may be a fluorine isotope
  • the present invention provides a method for the preparation of 8'-[ 3 H]rotenone as shown in the chemical synthesis scheme in FIG. 1.
  • the present invention provides a method for the preparation of an 8'-halorotenone as shown in the chemical synthesis scheme in FIG. 2.
  • the present invention provides a method for the preparation of 12-deoxy-12-fluoroamorphigenin as shown in the chemical synthesis scheme in FIG. 3.
  • the present invention provides a method for the preparation of 12-deoxy-12-fluororotenone as shown in the chemical synthesis scheme in FIG. 4.
  • the present invention provides a composition comprising a compound of the present invention and a pharmaceutically acceptable vehicle.
  • the composition is an injectible composition.
  • the vehicle is human serum albumin; aqueous buffer solutions, e.g. tris (hydromethyl) aminomethane (and its salts), phosphate, citrate, bicarbonate, alcohols, including ethanol, etc; sterile water; physiological saline; or balanced ionic solutions containing chloride and or dicarbonate salts or normal blood plasma cations such as calcium, potassium, sodium, and magnesium.
  • the concentration of a labeled compound as described herein is about 1.0 to 50 millicuries. In some embodiments the concentration is about 1.0 to 10, 10 to 20, 20 to 30, 30 to 40, or 40 to 50 millicuries.
  • the present invention provides a kit comprising, in suitable container means, at least one rotenone analog compound of the present invention.
  • the rotenone analog may be provided in the kit as a labeled rotenone analog or it may be provided as an unlabelled intermediate compound.
  • a diagnostic kit of the present invention may comprise, for example, a labeled rotenone analog and a pharmaceutically acceptable vehicle.
  • the kit may have a single container means or it may have distinct container means for each compound.
  • the diagnostic kit may further comprise a syringe or other device for administering a labeled rotenone analog and a pharmaceutically acceptable vehicle to a subject.
  • the diagnostic kit may further comprise instructions for using the components of the kit.
  • the present invention provides a method of imaging a region in a patient comprising: (a) administering to a patient a diagnostically effective amount of a composition comprising a labeled rotenone analog and a pharmaceutically effective vehicle; (b) exposing a region of the patient to radiation; and (c) obtaining an image of the region of the patient.
  • the region is the heart. In other aspects of the invention the region is the brain.
  • the composition is administered in a volume of about 1 to 10 mL.
  • the concentration of the labeled rotenone analog administered to the patient is about 1.0 to 50 millicuries. In some embodiments the concentration is about 1.0 to 10, 10 to 20, 20 to 30, 30 to 40, or 40 to 50 millicuries.
  • the composition is administered by intravenous injection.
  • the present invention provides a method of imaging blood flow in a patient comprising: (a) administering to a patient a diagnostically effective amount of a composition comprising a labeled rotenone analog and a pharmaceutically effective vehicle; (b) exposing the patient to radiation; and (c) obtaining an image of the patient.
  • the image may be of the patient's whole body or it may be a region of the patient such as the heart or brain.
  • the composition is administered in a volume of about 1 to 10 mL.
  • the concentration of the labeled rotenone analog administered to the patient is about 1.0 to 50 millicuries. In some embodiments the concentration is about 1.0 to 10, 10 to 20, 20 to 30, 30 to 40, or 40 to 50 millicuries.
  • the composition is administered by intravenous injection.
  • FIG. 1 shows a synthetic pathway in accordance with one embodiment of the present invention for the synthesis of 8'-[ 3 H]rotenone.
  • FIG. 2 shows a synthetic pathway in accordance with one embodiment of the present invention for the synthesis of 8'-halorotenone, including radiohalogenated compounds.
  • the 8'-halorotenone can be an 8'-chlororotenone, 8'-iodorotenone, 8'- bromorotenone, or 8'-fluororotenone.
  • FIG. 3 shows a synthetic pathway in accordance with one embodiment of the present invention for the synthesis of 12-Fluoro-deoxyamorphigenin.
  • FIG. 4 shows a synthetic pathway in accordance with one embodiment of the present invention for the synthesis of 12-Fluoro-deoxyrotenone.
  • Rotenone is a natural product of the Leguminosae plant family and has been used as an insecticide, pesticide and fish poison, and has been used in mitochondrial energy metabolism studies.
  • Rotenone is a specific, high-affinity inhibitor of Complex I (NADH ubiquinone oxidoreductase), the proximal enzyme of the mitochondrial electron transport chain. Since rotenone inhibition defines the activity of Complex I, defects in radiotracer binding can be expected to reflect functional changes in the enzyme, and hence, abnormalities of the mitochondrial energy metabolism.
  • the present invention provides novel rotenone analogs labeled with halogen isotopes or carbon isotopes.
  • the rotenone analogs of the present invention are useful in, for example, clinical imaging applications as tracers to measure cardiac blood flow and detect regions of ischemia.
  • the rotenone analogs disclosed herein have superior extraction and retention properties to other tracers (e.g., 99m Tc-sestamibi and 99m Tc- tetrofosmin) currently in clinical use.
  • the rotenone analogs may be labeled with halogen isotopes.
  • halogen isotopes include, 18 F, 19 F, 35 Cl, 37 Cl, 75 Br, 76 Br, 77 Br, 79 Br, 80 Br, 80m Br, 81 Br, 120 I, 121 I, 122 I, 123 I, 124 I, 125 I, 127 I, and 131 I.
  • Other isotopes that may be used with the compounds of the present invention include, for example, 11 C 73 Se, and 75 Se.
  • the terminal haloolefm group of rotenone is a useful functionality in the design of mechanism based radiotracers. Because the potency of these tracers often depends on the geometry of the olefin, there is considerable interest in developing stereospecific methods for these molecules.
  • novel rotenone analogs may be prepared according to the schemes shown in FIG. 1, FIG. 2, and FIG. 3.
  • heteroatom as used herein means an atom of any element other than carbon or hydrogen.
  • electron- withdrawing group is recognized in the art, and denotes the tendency of a substituent to attract valence electrons from neighboring atoms, i.e., the substituent is electronegative with respect to neighboring atoms.
  • a quantification of the level of electron-withdrawing capability is given by the Hammett sigma (o) constant. This well known constant is described in many references, for instance,
  • alkyl refers to saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.
  • a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e. g., C1-C30 for straight chain, C3-C30 for branched chain), and more preferably 20 or fewer.
  • preferred cycloalkyls have from 3-10 carbon atoms in their ring structure, and more preferably have 5, 6 or 7 carbons in the ring structure.
  • lower alkyl as used herein means an alkyl group, as defined above, but having from one to ten carbons, more preferably from one to six carbon atoms in its backbone structure. Likewise, “lower alkenyl” and “lower alkynyl” have similar chain lengths. Preferred alkyl groups are lower alkyls. In preferred embodiments, a substituent designated herein as alkyl is a lower alkyl.
  • aralkyl refers to an alkyl group substituted with an aryl group (e.g., an aromatic or heteroaromatic group).
  • alkenyl and alkynyl refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
  • aryl as used herein includes 5-, 6- and 7- membered single -ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like.
  • aryl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycles" or “heteroaromatics.”
  • the aromatic ring can be substituted at one or more ring positions with such substituents as described above, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties,-CF3,-CN, or the like.
  • aryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are "fused rings") wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls.
  • ortho, meta and para apply to 1,2-, 1, 3 -and 1 ,4-disubstituted benzenes, respectively.
  • the names 1, 2-dimethylbenzene and ortho- dimethylbenzene are synonymous.
  • heterocyclyl or “heterocyclic group” refer to 3-to 10-membered ring structures, more preferably 3-to 7-membered rings, whose ring structures include one to four heteroatoms. Heterocycles can also be polycycles.
  • Heterocyclyl groups include, for example, azetidine, azepine, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine , isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cimnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phen
  • the heterocyclic ring can be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety,-CF3,-CN, or the like.
  • substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, sily
  • polycyclyl or “polycyclic group” refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) in which two or more carbons are common to two adjoining rings, e.g., the rings are "fused rings".
  • Rings that are joined through non-adjacent atoms are termed "bridged” rings.
  • Each of the rings of the polycycle can be substituted with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety,- CF3, -CN, or the like.
  • carrier refers to an aromatic or non-aromatic ring in which each atom of the ring is carbon.
  • nitro means -N02 ; the term “halogen” designates- F,-C1, -Br or-I ; the term “sulfhydryl” means -SH ; the term “hydroxyl” means-OH; and the term “sulfonyl” means -SO2-.
  • amine and “amino” are art-recognized and refer to both unsubstituted and substituted amines, e.g., a moiety that can be represented by the general formula:
  • R 9 , Ri 0 - and R'io each independently represent a group permitted by the rules of valence.
  • acylamino is art-recognized and refers to a moiety that can be represented by the general formula:
  • Rg is as defined above, and R'n represents a hydrogen, an alkyl, an alkenyl or -(CH 2 ) m -R8, where m and Rg are as defined above.
  • amino is art recognized as an amino-substituted carbonyl and includes a moiety that can be represented by the general formula:
  • alkylthio refers to an alkyl group, as defined above, having a sulfur radical attached thereto.
  • the "alkylthio" moiety is represented by one of -S-alkyl, -S-alkenyl, -S-alkynyl, and -S-(CH 2 )Hi-Rs, wherein m and Rg are defined above.
  • Representative alkylthio groups include methylthio, ethyl thio, and the like.
  • carbonyl is art recognized and includes such moieties as can be represented by the general formula:
  • X is a bond or represents an oxygen or a sulfur
  • Rn represents a hydrogen, an alkyl, an alkenyl, -(CH 2 ) m -R8 or a pharmaceutically acceptable salt
  • R'u represents a hydrogen, an alkyl, an alkenyl or -(CH 2 ) m -R 8 , where m and Rg are as defined above.
  • X is an oxygen and Rn or R'n is not hydrogen
  • the formula represents an "ester”.
  • X is an oxygen, and Rn is as defined above, the moiety is referred to herein as a carboxyl group, and particularly when Rn is a hydrogen, the formula represents a "carboxylic acid".
  • alkoxyl or "alkoxy” as used herein refer to an alkyl group, as defined above, having an oxygen radical attached thereto.
  • Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like.
  • An "ether” is two hydrocarbons covalently linked by an oxygen. Accordingly, the substituent of an alkyl that renders that alkyl an ether is or resembles an alkoxyl, such as can be represented by one of -O-alkyl,-O- alkenyl, -O-alkynyl, -O-(CH 2 ) m -R 8 , where m and Rs are described above.
  • R 41 is an electron pair, hydrogen, alkyl, cycloalkyl, or aryl.
  • triflyl, tosyl, mesyl, and nonaflyl are art-recognized and refer to trifluoromethanesulfonyl, p-toluenesulfonyl, methanesulfonyl, and nonafluorobutanesulfonyl groups, respectively.
  • triflate, tosylate, mesylate, and nonaflate are art-recognized and refer to trifluoromethanesulfonate ester, p- toluenesulfonate ester, methanesulfonate ester, and nonafluorobutanesulfonate ester functional groups and molecules that contain said groups, respectively.
  • Me, Et, Ph, Tf, Nf, Ts, Ms represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl, p-toluenesulfonyl and methanesulfonyl, respectively.
  • a more comprehensive list of the abbreviations utilized by organic chemists of ordinary skill in the art appears in the first issue of each volume of the Journal of Organic Chemistry; this list is typically presented in a table entitled Standard List of Abbreviations, the contents of which are hereby incorporated by reference in its entirety for all purposes.
  • sulfonyl refers to a moiety that can be represented by the general formula:
  • R 44 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.
  • sulfoxido refers to a moiety that can be represented by the general formula:
  • R 44 in which R 44 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aralkyl, or aryl.
  • a “selenoalkyl” refers to an alkyl group having a substituted seleno group attached thereto.
  • Exemplary “selenoethers” which may be substituted on the alkyl are selected from one of -Se-alkyl, -Se-alkenyl, -Se-alkynyl, and-Se-(CH 2 ) m -R7, m and R 7 being defined above.
  • Analogous substitutions can be made to alkenyl and alkynyl groups to produce, for example, aminoalkenyls, aminoalkynyls, amidoalkenyls, amidoalkynyls, iminoalkenyls, iminoalkynyls, thioalkenyls, thioalkynyls, carbonyl-substituted alkenyls or alkynyls.
  • each expression e. g. alkyl, m, n, etc., when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.
  • substitution or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • the term "substituted" is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds.
  • Illustrative substituents include, for example, those described herein above.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.
  • protecting group P g
  • P g protecting group
  • protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively.
  • a list of illustrative, but not exhaustive protecting groups is disclosed in Greene and
  • Contemplated equivalents of the compounds described above include compounds which otherwise correspond thereto, and which have the same general properties thereof (e. g. , functioning as analgesics), wherein one or more simple variations of substituents are made which do not adversely affect the efficacy of the compound in binding receptors.
  • the compounds of the present invention may be prepared by the methods illustrated in the general reaction schemes as, for example, described below, or by modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are in themselves known, but are not mentioned here.
  • the present invention also relates to imaging agents containing a radionuclide as described above, in an amount sufficient for imaging, together with a pharmaceutically acceptable vehicle.
  • Imaging agents incorporating a gamma-emitting nuclide which, because of physical or metabolic properties of its coordinated ligands, localize in a specific organ after they are administered to the patient.
  • the resultant images can reflect organ structure or function.
  • the radiolabel is a gamma-radiation emitting radionuclide and the radiotracer is located using a gamma- radiation detecting camera (this process is often referred to as gamma scintigraphy).
  • the imaged site is detectable because the radiotracer is chosen either to localize at a pathological site (termed positive contrast) or, alternatively, the radiotracer is chosen specifically not to localize at such pathological sites (termed negative contrast).
  • a variety of radionuclides are known to be useful for radioimaging, including Ga- 67, Tc-99m, In-IU, 1-123, 1-125, Yb-169, and Re-186.
  • radiological vehicles include, human serum albumin; aqueous buffer solutions, e.g tris (hydromethyl) aminomethane (and its salts), phosphate, citrate, bicarbonate, alcohols, including ethanol, etc; sterile water; physiological saline; and balanced ionic solutions containing chloride and or dicarbonate salts or normal blood plasma cations such as calcium, potassium, sodium, and magnesium.
  • the concentration of the imaging agent according to the present invention in the radiological vehicle should be sufficient to provide satisfactory imaging, for example, when using an aqueous solution, the dosage is about 1.0 to 50 millicuries.
  • the imaging agent should be administered so as to remain in the patient for about 1 to 3 hours, although both longer and shorter time periods are acceptable. Therefore, convenient ampules containing 1 to 10 mL of aqueous solution may be prepared.
  • Labeled rotenone analogs of the present invention may be used with imaging techniques such as positron emission tomography (PET) and Single Photon Emission Computed Tomography (SPECT).
  • PET imaging is a diagnostic examination that involves the acquisition of physiologic images based on the detection of radiation from the emission of positrons from a radionuclide compound administered to the patient. The radionuclide compound is typically administered via intravenous injection. Different colors or degrees of brightness on a PET image represent different levels of tissue or organ function.
  • SPECT imaging is a three-dimensional technique combined with computer assisted reconstruction of images of organs to reveal both anatomy and function. As with PET imaging, patients undergoing SPECT imaging are administered a radioactive tracer.
  • PET and SPECT images may be used to evaluate a variety of diseases, and are commonly used in the fields of oncology, cardiology, and neurology.
  • rotenone has high affinity to Complex I of the mitochondrial electron transport chain.
  • labeled rotenone analogs may be used to investigate abnormalities in mitochondrial function. Such abnormalities may be associated with, for example, ischemia. Due to its affinity for mitochondria, rotenone is particularly well suited for use with tissues rich in mitochondria, such as the myocardium and brain.
  • PET or SPECT scans of the heart using rotenone radionulcides can be used to determine blood flow to the heart muscle and help evaluate signs of coronary artery disease. This information can assist health care providers in the diagnosis, localization, and risk stratification of patients with known or suspected coronary artery disease.
  • Complex I NADH-quinone oxidoreductase
  • Complex I is one of three energy-transducing enzyme complexes of the respiratory chain in mitochondria. It is the point of entry for the major fraction of electrons that traverse the respiratory chain eventually resulting in the reduction of oxygen.
  • Mammalian Complex I is composed of 46 subunits and contains noncovalently bound FMN and several iron-sulfur clusters as prosthetic groups.
  • novel rotenone analogs of the present invention provide valuable research tools for the study of Complex I and associated pathologies.
  • the novel rotenone analogs can be used as in vitro, in situ, or in vivo markers of Complex I.
  • compositions in accordance with certain embodiment of the present invention comprise an effective amount of one or more of the rotenone radionuclides described above and formulated together with one or more pharmaceutically acceptable carriers and/or diluents.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • materials which can serve as pharmaceutically-acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15)
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms upon the subject compounds may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
  • kits will thus comprise, in suitable container means, at least one rotenone analog and/or rotenone analog intermediate.
  • the kits will generally include at least one vial, test tube, flask, bottle, syringe or other container, into which a component may be placed, and preferably, suitably aliquoted. Where there is more than one component in the kit, the kit also will generally contain a second, third or other additional container into which the additional components may be separately placed. However, various combinations of components may be comprised in a container. Such kits may be useful in diagnostic and/or research purposes.
  • a diagnostic kit of the present invention may comprise a labeled rotenone analog and a pharmaceutically acceptable vehicle.
  • the diagnostic kit of the present invention may comprise an unlabeled rotenone analog intermediate.
  • the kit may have a single container means or it may have distinct container means for each compound.
  • the diagnostic kit may further comprise a syringe or other device for administering the labeled rotenone analog and a pharmaceutically acceptable vehicle to a subject.
  • the diagnostic kit may further comprise instructions for using the components of the kit.
  • PhSeBr, PhSeI, or PhSeF respectively.
  • the reaction is allowed to warm to room temperature, water is added (100 mL) and the mixture extracted with dichloromethane (3 x 50 mL). The extracts are washed with brine, dried over Na 2 SO 4 , filtered and evaporated to provide the crude 12-hydroxyamorphigenin or 12- hydroxyrotenol.
  • TsCl (282 mg, 1.48 mmol) is added to an 0 0 C solution of 12-hydroxyamorphigenin or 12-hydroxyrotenol (280 mg) and pyridine (0.12 ml, 1.48 mmol) in dry CH 2 Cl 2 (4 ml).
  • the flask is capped and kept in the refrigerator for 48 h.
  • the mixture is poured onto a short silica gel column and eluted with 1 :9 EtOAc: CH 2 Cl 2 to remove the excess TsCl and pyridine.
  • nBu 4 NF (2.6 ml, 1.0 M solution in THF, 2.6 mmol) is added to a solution of 12-(p-Toluenesulfonyloxy)-amorphigenin or 12-(p-Toluenesulfonyloxy)-rotenol (500 mg) in CH3CN (15 ml).
  • the solution is refluxed under argon for 2 h and then allowed to cool to room temperature.
  • the reaction mixture is diluted with a 1 :4 CH 2 Cl 2 :hexane solution and passed through a short silica gel column to remove very polar materials.
  • [F-18]radiofluorination of rotenoid O-tosylates [F-18]tetra-n- butylammonium fluoride as a solution in anhydrous acetonitrile (450 uL) is added to 12-(p-Toluenesulfonyloxy)-amorphigenin or 12-(p-Toluenesulfonyloxy)-rotenol (1.5 mg), and the reaction vial is capped and heated at 100 0 C in an oil bath for 20 minutes.
  • the crude reaction mixture is filtered through a short plug of silica to remove unreacted [F-18]fluoride, and the solvent is removed at 100 0 C under a stream of nitrogen to provide the crude [F-18]12-fluoro-deoxyamorphigenin or [F- 18] 12-fluoro- deoxyrotenone..
  • the compounds of present invention are evaluated as blood flow tracers according to methods described in VanBrocklin et al. (U.S. Application No. 60/682,621) for evaluating Z-V- iodorotenol, E-7'-iodorotenol, Z-7'-iodorotenone, and E-7'-iodorotenone compounds.
  • the 8'-[ 3 H]rotenone, radiohalgoenated 8'halorotenone, radiohalogenated 12- fluoro-deoxymorphigenin, or radiohalogenated 12-fluoro-deoxyrotenone compounds are also evaluated in canines. Two 20-25 kg dogs are anesthetized with iv sodium pentathol and maintained on inhaled isoflurane. Four to six mCi of 8'-[ 3 H]rotenone, radiohalgoenated 8'halorotenone, radiohalogenated 12-fluoro-deoxymorphigenin, or radiohalogenated 12-fluoro-deoxyrotenone are injected in a front leg vein. Dual head planar imaging is carried out using the GE Millenium SPECT scanner with Hawkeye xray CT. The scanning protocol is serial 4 m whole body scans over the first hour,
  • compositions and methods of this invention have been described in terms of particular embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and methods and in the steps or in the sequence of steps of the methods described herein without departing from the concept, spirit and scope of the invention. More specifically, it will be apparent that certain agents which are both chemically and physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.

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Abstract

La présente invention porte sur des analogues de roténone et des procédés de fabrication et d'utilisation de ceux-ci. Marqué par des isotopes émettant des photons et des positrons, les analogues de roténone de la présente invention sont utiles, par exemple, dans des applications d'imagerie clinique sous forme de traceurs pour mesurer un flux de sang cardiaque et détecter des régions d'ischémie. Les analogues de roténone décrits ici ont des propriétés d'extraction et de rétention supérieures à d'autres traceurs (par exemple, 99mTc-sestamibi et 99mTc-tétrofosmine) couramment utilisés en clinique.
PCT/US2007/084870 2006-11-15 2007-11-15 Analogues de roténone marqués Ceased WO2008133730A2 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102399230A (zh) * 2010-09-07 2012-04-04 湖南大学 N-酰基吡唑鱼藤醚及其制备方法与应用
WO2013006958A1 (fr) 2011-07-13 2013-01-17 Nordion (Canada) Inc. Dérivés de roténone radio-marqués et leur utilisation en imagerie spect

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003086476A1 (fr) * 2002-04-08 2003-10-23 Biostream, Inc. Derives de rotenone a marquage au technetium, et procedes d'utilisation correspondants
US7485283B2 (en) * 2004-04-28 2009-02-03 Lantheus Medical Imaging Contrast agents for myocardial perfusion imaging

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102399230A (zh) * 2010-09-07 2012-04-04 湖南大学 N-酰基吡唑鱼藤醚及其制备方法与应用
CN102399230B (zh) * 2010-09-07 2013-08-28 湖南大学 N-酰基吡唑鱼藤醚及其制备方法与应用
WO2013006958A1 (fr) 2011-07-13 2013-01-17 Nordion (Canada) Inc. Dérivés de roténone radio-marqués et leur utilisation en imagerie spect
US20130022542A1 (en) * 2011-07-13 2013-01-24 Nordion (Canada) Inc. Radiolabelled rotenone derivatives and their use in spect imaging
JP2014520821A (ja) * 2011-07-13 2014-08-25 ノルディオン （カナダ） インク． 放射標識されたロテノン誘導体及びこれらのｓｐｅｃｔ画像化における使用
US9133208B2 (en) 2011-07-13 2015-09-15 Nordion (Canada) Inc. Radiolabelled rotenone derivatives and their use in SPECT imaging

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