Phosphodiesterase 10A PET Radioligand Development Program: From Pig to Human

Four novel phosphodiesterase 10A (PDE10A) PET tracers have been synthesized, characterized in preclinical studies, and compared with the previously reported C-11-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 C-11 via N-methylation or with F-18 through an S(N)2 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, C-11-IMA106 and C-11-IMA107 were taken into further evaluation and comparison with C-11-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 C-11-IMA107 and C-11-MP-10 displayed the most favorable tissue kinetics and imaging properties. The administration of selective PDE10A inhibitors reduced the binding of C-11-IMA107 and C-11-MP-10 in the PDE10A-rich brain regions, in a dose-dependent manner. In the nonhuman primate brain, the tissue kinetics of C-11-IMA107 and C-11-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: C-11-IMA107 was identified as the ligand with the highest binding potential while still possessing reversible kinetics. The first human administration of C-11-IMA107 has demonstrated the expected regional distribution and suitably fast kinetics, indicating that C-11-IMA107 will be a useful tool for the investigation of PDE10A status in the living human brain.