Radiosynthesis and in vivo evaluation of [¹¹C]MP-10 as a positron emission tomography radioligand for phosphodiesterase 10A

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• 作者：Christophe Plisson^a ; ^{Christophe.2.plisson@gsk.com"" rel=""nofollow} ; Cristian Salinas^a ; David Weinzimmer^c ; David Labaree^c ; Shu-Fei Lin^c ; Yu-Shin Ding^c ; Steen Jakobsen^b ; Paul W. Smith^a ; Kawanishi Eiji^d ; Richard E. Carson^c ; Roger N. Gunn^a ; Eugenii A. Rabiner^a
• 关键词：PET ; PDE10A ; MP-10 ; Carbon-11 ; In vivo ; Brain
• 刊名：Nuclear Medicine and Biology
• 出版年：2011
• 出版时间：August 2011
• 年：2011
• 卷：38
• 期：6
• 页码：875-884
• 全文大小：354 K

文摘

Introduction

The aim of this study was to evaluate a newly reported positron emission tomography (PET) radioligand [¹¹C]MP-10, a potent and selective inhibitor of the central phosphodiesterase 10A enzyme (PDE10A) in vivo, using PET.

Methods

A procedure was developed for labeling MP-10 with carbon-11. [¹¹C]MP-10 was evaluated in vivo both in the pig and baboon brain.

Results

Alkylation of the corresponding desmethyl compound with [¹¹C]methyl iodide produced [¹¹C]MP-10 with good radiochemical yield and specific activity. PET studies in the pig showed that [¹¹C]MP-10 rapidly entered the brain reaching peak tissue concentration at 1–2 min postadministration, followed by washout from the tissue. Administration of a selective PDE10A inhibitor reduced the binding in all brain regions to the levels of the cerebellum, demonstrating the saturability and selectivity of [¹¹C]MP-10 binding. In the nonhuman primate, the brain tissue kinetics of [¹¹C]MP-10 were slower, reaching peak tissue concentrations at 30–60 min postadministration. In both species, the observed rank order of regional brain signal was striatum>diencephalon>cortical regions=cerebellum, consistent with the known distribution and concentration of PDE10A. [¹¹C]MP-10 brain kinetics were well described by a two-tissue compartment model, and estimates of total volume of distribution (V_T) were obtained. Blocking studies with unlabeled MP-10 revealed the suitability of the cerebellum as a reference tissue and enabled the estimation of regional binding potential (BP_ND) as the outcome measure of specific binding. Quantification of [¹¹C]MP-10 binding using the simplified reference tissue model with cerebellar input function produced BP_ND estimates consistent with those obtained by the two-tissue compartment model.

Conclusion

We demonstrated that [¹¹C]MP-10 possesses good characteristics for the in vivo quantification of the PDE10A in the brain by PET.