Evaluation of [18F]fluoroxanomeline {5-{4-[(6-[18F]fluorohexyl)oxy]-1,2,5-thiadiazol-3-yl}-1-methyl-1,2,3,6-tetrahydropyridine} in muscarinic knockout mice

Kiesewetter, Dale O.; Jagoda, Elaine M.; Shimoji, Kazuaki; Ma, Ying; Eckelman, William C.

doi:10.1016/j.nucmedbio.2006.11.002

Cited by 5 publications

(6 citation statements)

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“…The syntheses of 19 derivatives of TZTP (Table 1) are reported, including previously known compounds (2a, 13 4a, 11,12 8a, 26 8b, 26 9c, 25 and 10 8 ). Syntheses of the TZTP analogs were carried out by literature procedures with modifications.…”

Section: Chemistrymentioning

confidence: 99%

“…24 While it was found that xanomeline increased cognitive function of patients with Alzheimer's disease, several side effects precluded its therapeutic use. Carbon-11 ( 11 C; t 1/2 = 20.4 min) labelled xanomeline was evaluated in human subjects 9,25 and a 18 Flabelled xanomeline derivative was evaluated in rodents 25 but neither radiopharmaceutical was further pursued because of inadequate receptor selectivity.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Towards the development of new subtype-specific muscarinic receptor radiopharmaceuticals — Radiosynthesis and ex vivo biodistribution of [¹⁸F]3-(4-(2-(2-(2-fluoroethoxy)ethoxy)ethylthio)-1,2,5-thiadiazol-3-yl)-1-methyl-1,2,5,6-tetrahydropyridine

et al. 2010

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Muscarinic receptors have been implicated in neurological disorders including Alzheimer's disease, Parkinson's disease, and schizophrenia. Nineteen derivatives of thiadiazolyltetrahydropyridine (TZTP), a core that has previously shown high affinities towards muscarinic receptor subtypes, were synthesized and evaluated via in vitro binding assays. The title compound, a fluoro-polyethyleneglycol analog of TZTP (4c), was subsequently labelled with fluorine-18. Fluorine-18-labelled 4c was produced, via an automated synthesis, in an average radiochemical yield of 36% (uncorrected for decay), with high radiochemical purity (>99%) and high specific activity (326 GBq/mmol; end-of-bombardment), within 40 min (n = 3). Ex vivo biodistribution studies following tail-vein injection of [ 18 F]4c in conscious rats displayed sufficient brain uptake (0.4%-0.7% injected dose / gram of wet tissue in all brain regions at 5 min post injection); however, there were substantial polar metabolites present in the brain, thereby precluding future use of [ 18 F]4c for imaging in the central nervous system. Key words: fluorine-18, muscarinic receptor, thiadiazolyltetrahydropyridine (TZTP), positron emission tomography (PET).Résumé : Les récepteurs muscariniques ont été impliqués dans des désordres neurologiques, dont la maladie d'Alzheimer, la maladie de Parkinson et la schizophrénie. On a réalisé la synthèse de dix-neuf dérivés de la thiadiazolyltétrahydropyri-dine (TZTP), un produit fondamental pour lequel des études antérieures ont permis de montrer de grandes affinités vis-à-vis des sous-types de récepteurs muscarinique, et on a évalué leurs propriétés par des essais de fixation in vitro. On a subséquemment marqué au fluor-18 le composé mentionné dans le titre (4c), un analogue fluoropolyéthylèneglycol de la TZTP. Le composé 4c marqué au fluor-18 a été obtenu, par le biais d'une synthèse automatisée, avec un rendement radiochimique de 36 % (non corrigé pour la décroissance), avec une pureté radiochimique élevée (>99 %) et une activité spéci-fique élevée (326 GBq/mmol; fin du bombardement), en moins de 40 minutes (n = 3). Des études de biodistribution ex vivo à la suite d'injectons dans la veine de la queue du [ 18 F]4c dans des rats conscients ont démontré qu'il y se produit une absorption suffisante par le cerveau (0,4 à 0,7 % de la dose injectée / gramme de tissu mouillé dans toutes les régions du cerveau cinq minutes après l'injection) ; toutefois, plusieurs métabolites polaires sont présents dans le cerveau et cette situation élimine l'usage dans le futur du [ 18 F]4c pour faire de l'imagerie du système nerveux central. Mots-clés :fluor-18, récepteur muscarinique, thiadiazolyltétrahydropyridine (TZTP), tomographie à émission de positon (TEP).[Traduit par la Rédaction]

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Section: Chemistrymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Towards the development of new subtype-specific muscarinic receptor radiopharmaceuticals — Radiosynthesis and ex vivo biodistribution of [¹⁸F]3-(4-(2-(2-(2-fluoroethoxy)ethoxy)ethylthio)-1,2,5-thiadiazol-3-yl)-1-methyl-1,2,5,6-tetrahydropyridine

et al. 2010

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“…In addition to labeling the total MACh‐R receptor pool, these antagonists are nonselective with regard to MACh‐R subtypes. The M1ACh‐R agonist that have been radiolabelled and evaluated, such as [ 11 C]xanomeline, [ 11 C]butylthio‐thiadiazolyltetrahydropyridine, and [ 18 F]fluoroxanomeline, are not fully selective for MACh‐R subtypes and also bind to σ‐sites …”

Section: Introductionmentioning

confidence: 99%

Radiosynthesis and biological evaluation of the M1 muscarinic acetylcholine receptor agonist ligand [¹¹C]AF150(S)

Buiter

Leysen

Schuit

et al. 2012

Labelled Comp Radiopharmac

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Purpose M1 muscarinic acetylcholine receptor (M1ACh‐R) agonists are potential therapeutics for cognitive disorders. The aim of this study was to develop an orthosteric agonist positron emission tomography (PET) ligand for the M1ACh‐R that would provide a tool to explore the active G‐protein coupled receptor. To that extend, the radiosynthesis, receptor binding in vitro, and brain uptake of [11C]AF150(S), a selective M1ACh‐R agonist, were investigated. Procedures [11C]AF150(S) was synthesized, its binding properties were investigated using autoradiography on rat brain sections, and brain uptake was determined in biodistribution studies ex vivo in rats. Metabolites in brain and blood were measured using high‐performance liquid chromatography. Results Yield of the [11C]AF150(S) radiosynthesis was 69 ± 9% with radiochemical purity >99%. The logDoct,7.4 was 0.05. Autoradiography showed binding in M1ACh‐R rich brain areas and selective inhibition by muscarinic agents in conditions promoting agonist binding. Biodistribution studies revealed rapid and high brain uptake, to levels exceeding five times the blood level. In M1ACh‐R rich areas, specific uptake versus cerebellum was apparent, remaining constant over 60 min in spite of rapid decline of radioactivity from the brain and rapid peripheral metabolism. Brain uptake of [11C]AF150(S) may involve facilitated transport. Conclusion [11C]AF150(S) was successfully synthesized, showed M1ACh‐R agonist binding properties, and high brain uptake. It provides an interesting lead for the development of an M1ACh‐R agonist PET ligand meant to explore the active receptor state. Copyright © 2012 John Wiley & Sons, Ltd.

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“…We also analyzed a second compound, an [ 18 F] analogue of xanomeline [26] in this thiadiazole series of muscarinic ligands, one that possesses some selectivity for M1. This compound differs structurally from FP-TZTP in that it lacks the side chain sulfur and has a longer alkyl chain.…”

Section: Metabolite Identificationmentioning

confidence: 99%

“…Rat, monkey and human hepatocytes produced a similar metabolite profile. We also compared the metabolism rate in hepatocytes of the three species using LC/MS and radio-chromatography and found that the relative metabolism rate is monkey > rat > human [26]. …”

Section: Metabolite Identificationmentioning

confidence: 99%

Applications of LC-MS in PET Radioligand Development and Metabolic Elucidation

Ma¹,

Kiesewetter²,

Lang³

et al. 2010

CDM

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Positron emission tomography (PET) is a very sensitive molecular imaging technique that when employed with an appropriate radioligand has the ability to quantititate physiological processes in a non-invasive manner. Since the imaging technique detects all radioactive emissions in the field of view, the presence and biological activity of radiolabeled metabolites must be determined for each radioligand in order to validate the utility of the radiotracer for measuring the desired physiological process. Thus, the identification of metabolic profiles of radiolabeled compounds is an important aspect of design, development, and validation of new radiopharmaceuticals and their applications in drug development and molecular imaging. Metabolite identification for different chemical classes of radiopharmaceuticals allows rational design to minimize the formation and accumulation of metabolites in the target tissue, either through enhanced excretion or minimized metabolism. This review will discuss methods for identifying and quantitating metabolites during the pre-clinical development of radiopharmaceuticals with special emphasis on the application of LC/MS.

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Evaluation of [18F]fluoroxanomeline {5-{4-[(6-[18F]fluorohexyl)oxy]-1,2,5-thiadiazol-3-yl}-1-methyl-1,2,3,6-tetrahydropyridine} in muscarinic knockout mice

Cited by 5 publications

References 48 publications

Towards the development of new subtype-specific muscarinic receptor radiopharmaceuticals — Radiosynthesis and ex vivo biodistribution of [¹⁸F]3-(4-(2-(2-(2-fluoroethoxy)ethoxy)ethylthio)-1,2,5-thiadiazol-3-yl)-1-methyl-1,2,5,6-tetrahydropyridine

Towards the development of new subtype-specific muscarinic receptor radiopharmaceuticals — Radiosynthesis and ex vivo biodistribution of [¹⁸F]3-(4-(2-(2-(2-fluoroethoxy)ethoxy)ethylthio)-1,2,5-thiadiazol-3-yl)-1-methyl-1,2,5,6-tetrahydropyridine

Radiosynthesis and biological evaluation of the M1 muscarinic acetylcholine receptor agonist ligand [¹¹C]AF150(S)

Applications of LC-MS in PET Radioligand Development and Metabolic Elucidation

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Evaluation of [18F]fluoroxanomeline {5-{4-[(6-[18F]fluorohexyl)oxy]-1,2,5-thiadiazol-3-yl}-1-methyl-1,2,3,6-tetrahydropyridine} in muscarinic knockout mice

Cited by 5 publications

References 48 publications

Towards the development of new subtype-specific muscarinic receptor radiopharmaceuticals — Radiosynthesis and ex vivo biodistribution of [18F]3-(4-(2-(2-(2-fluoroethoxy)ethoxy)ethylthio)-1,2,5-thiadiazol-3-yl)-1-methyl-1,2,5,6-tetrahydropyridine

Towards the development of new subtype-specific muscarinic receptor radiopharmaceuticals — Radiosynthesis and ex vivo biodistribution of [18F]3-(4-(2-(2-(2-fluoroethoxy)ethoxy)ethylthio)-1,2,5-thiadiazol-3-yl)-1-methyl-1,2,5,6-tetrahydropyridine

Radiosynthesis and biological evaluation of the M1 muscarinic acetylcholine receptor agonist ligand [11C]AF150(S)

Applications of LC-MS in PET Radioligand Development and Metabolic Elucidation

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Towards the development of new subtype-specific muscarinic receptor radiopharmaceuticals — Radiosynthesis and ex vivo biodistribution of [¹⁸F]3-(4-(2-(2-(2-fluoroethoxy)ethoxy)ethylthio)-1,2,5-thiadiazol-3-yl)-1-methyl-1,2,5,6-tetrahydropyridine

Towards the development of new subtype-specific muscarinic receptor radiopharmaceuticals — Radiosynthesis and ex vivo biodistribution of [¹⁸F]3-(4-(2-(2-(2-fluoroethoxy)ethoxy)ethylthio)-1,2,5-thiadiazol-3-yl)-1-methyl-1,2,5,6-tetrahydropyridine

Radiosynthesis and biological evaluation of the M1 muscarinic acetylcholine receptor agonist ligand [¹¹C]AF150(S)