Radiosynthesis and in vivo evaluation of [11C]MP-10 as a PET probe for imaging PDE10A in rodent and non-human primate brain

Structure and microPET image of [11C]MP-10. 2-((4-(1-[11C]Methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)-quinoline (MP-10), a specific PDE10A inhibitor (IC50=0.18nM with 100-fold selectivity over other PDEs), was radiosynthesized by alkylation of the desmethyl precursor with [11C]CH3I, ∼45%...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2011-03, Vol.19 (5), p.1666-1673
Main Authors: Tu, Zhude, Fan, Jinda, Li, Shihong, Jones, Lynne A., Cui, Jinquan, Padakanti, Prashanth K., Xu, Jinbin, Zeng, Dexing, Shoghi, Kooresh I., Perlmutter, Joel S., Mach, Robert H.
Format: Article
Language:English
Subjects:
Alkylation
Animals
Biological and medical sciences
Blood-Brain Barrier
Brain
Brain - diagnostic imaging
Brain - metabolism
Carbon-11
Cerebellum
Contrast media. Radiopharmaceuticals
Haplorhini
Huntington’s disease
Male
Medical sciences
Metabolites
MP-10
Neostriatum
Neuroimaging
PDE10A
PET imaging
Pharmacology. Drug treatments
Positron emission tomography
Positron-Emission Tomography - methods
Primates
Probes
Pyrazoles - chemical synthesis
Pyrazoles - chemistry
Quinolines - chemical synthesis
Quinolines - chemistry
Radiopharmaceuticals - chemical synthesis
Rats
Rats, Sprague-Dawley
Tissue Distribution
Tracers
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Summary:Structure and microPET image of [11C]MP-10. 2-((4-(1-[11C]Methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)-quinoline (MP-10), a specific PDE10A inhibitor (IC50=0.18nM with 100-fold selectivity over other PDEs), was radiosynthesized by alkylation of the desmethyl precursor with [11C]CH3I, ∼45% yield, >92% radiochemical purity, >370GBq/μmol specific activity at end of bombardment (EOB). Evaluation in Sprague–Dawley rats revealed that [11C]MP-10 had highest brain accumulation in the PDE10A enriched-striatum, the 30min striatum: cerebellum ratio reached 6.55. MicroPET studies of [11C]MP-10 in monkeys displayed selective uptake in striatum. However, a radiolabeled metabolite capable of penetrating the blood–brain-barrier may limit the clinical utility of [11C]MP-10 as a PDE10A PET tracer.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2011.01.032