Phosphodiesterase 10a pet radioligand development program: From pig to human

Christophe Plisson, David Plisson, Steen Jakobsen, Sridhar Natesan, Cristian Salinas, Shu Fei Lin, David Labaree, Ming Qiang Zheng, Nabeel Nabulsi, Tiago Reis Marques, Shitij Kapur, Eiji Kawanishi, Takeaki Saijo, Roger N. Gunn, Richard E. Carson, Eugenii A. Rabiner

Research output: Contribution to journalArticlepeer-review

47 Citations (Scopus)


Four novel phosphodiesterase 10A (PDE10A) PET tracers have been synthesized, characterized in preclinical studies, and compared with the previously reported 11C-MP-10. Methods: On the basis of in vitro data, IMA102, IMA104, IMA107, and IMA106 were identified as potential PDE10A radioligand candidates and labeled with either 11C via N-methylation or with 18F through an SN2 reaction, in the case of IMA102. These candidates were compared with 11C-MP-10 in pilot in vivo studies in the pig brain. On the basis of these data, 11C-IMA106 and 11C-IMA107 were taken into further evaluation and comparison with 11C-MP-10 in the primate brain. Finally, the most promising radioligand candidate was progressed into human evaluation. Results: All 5 tracers were produced with good radiochemical yield and specific activity. All candidates readily entered the brain and demonstrated a heterogeneous distribution consistent with the known expression of PDE10A. Baseline PET studies in the pig and baboon showed that 11C-IMA107 and 11C-MP-10 displayed the most favorable tissue kinetics and imaging properties. The administration of selective PDE10A inhibitors reduced the binding of 11C-IMA107 and 11C-MP-10 in the PDE10A-rich brain regions, in a dose-dependent manner. In the nonhuman primate brain, the tissue kinetics of 11CIMA107 and 11C-MP-10 were well described by a 2-tissue-compartment model, allowing robust estimates of the regional total volume of distribution. Blockade with unlabeled MP-10 confirmed the suitability of the cerebellum as a reference tissue and enabled the estimation of regional binding potential as the outcome measure of specific binding. Conclusion: 11C-IMA107 was identified as the ligand with the highest binding potential while still possessing reversible kinetics. The first human administration of 11C-IMA107 has demonstrated the expected regional distribution and suitably fast kinetics, indicating that 11C-IMA107 will be a useful tool for the investigation of PDE10A status in the living human brain.

Original languageEnglish
Pages (from-to)595-601
Number of pages7
JournalJournal of Nuclear Medicine
Issue number4
Publication statusPublished - Apr 1 2014
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Radiology Nuclear Medicine and imaging


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