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. 2011 Mar 1;19(5):1666-73.
doi: 10.1016/j.bmc.2011.01.032. Epub 2011 Jan 22.

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

Zhude Tu  1 , Jinda Fan, Shihong Li, Lynne A Jones, Jinquan Cui, Prashanth K Padakanti, Jinbin Xu, Dexing Zeng, Kooresh I Shoghi, Joel S Perlmutter, Robert H Mach
Affiliations

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

Zhude Tu et al. Bioorg Med Chem. .

Abstract

2-((4-(1-[(11)C]Methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)-quinoline (MP-10), a specific PDE10A inhibitor (IC(50)=0.18 nM with 100-fold selectivity over other PDEs), was radiosynthesized by alkylation of the desmethyl precursor with [(11)C]CH(3)I, ∼45% yield, >92% radiochemical purity, >370 GBq/μmol specific activity at end of bombardment (EOB). Evaluation in Sprague-Dawley rats revealed that [(11)C]MP-10 had highest brain accumulation in the PDE10A enriched-striatum, the 30 min striatum: cerebellum ratio reached 6.55. MicroPET studies of [(11)C]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 [(11)C]MP-10 as a PDE10A PET tracer.

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Figures

Figure 1
Figure 1
The striatum versus non-target tissue ratios of [11C]MP-10 in were calculated by using the %ID/g.
Figure 2
Figure 2
Upper Panel: MicroPET images (left), co-registered images (middle) and MRI images (right), High uptake of [11C]MP-10 in striatum was observed which gave clear visualization of tracer in putamen and caudate; Lower Panel: Tissue time-activity curves for caudate, putamen and cerebellum (left); Target : non-target ratios (right).
Figure 3
Figure 3
HPLC results of rat plasma and brain tissue at 60 min post-i.v. injection of [11C]MP-10. Metabolite #1 that is the major metabolite in both plasma and brain tissue has the capability of crossing the brain-blood-barrier and enter into the brain.
Figure 4
Figure 4
HPLC results of monkey arterial blood plasma at 5, 15, 30 and 60 min post-i.v. injection of [11C]MP-10 into monkeys. Only one metabolite with retention time as 3 min was observed and it matched the metabolite #1 in the rat plasma and brain tissue post-i.v. injection of [11C]MP-10. This metabolite has the capability of crossing the brain-blood-barrier and entering into the brain.
Scheme 1
Scheme 1
Synthesis of MP-10
Scheme 2
Scheme 2
Synthesis of [11C]MP-10
Scheme 3
Scheme 3
O-dealkylation of [11C]MP-10
See this image and copyright information in PMC

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