PT  - JOURNAL ARTICLE
AU  - Christophe Plisson
AU  - David Weinzimmer
AU  - Steen Jakobsen
AU  - Sridhar Natesan
AU  - Cristian Salinas
AU  - Shu-Fei Lin
AU  - David Labaree
AU  - Ming-Qiang Zheng
AU  - Nabeel Nabulsi
AU  - Tiago Reis Marques
AU  - Shitij Kapur
AU  - Eiji Kawanishi
AU  - Takeaki Saijo
AU  - Roger N. Gunn
AU  - Richard E. Carson
AU  - Eugenii A. Rabiner
TI  - Phosphodiesterase 10A PET Radioligand Development Program: From Pig to Human
AID  - 10.2967/jnumed.113.131409
DP  - 2014 Apr 01
TA  - Journal of Nuclear Medicine
PG  - 595--601
VI  - 55
IP  - 4
4099  - http://jnm.snmjournals.org/content/55/4/595.short
4100  - http://jnm.snmjournals.org/content/55/4/595.full
SO  - J Nucl Med2014 Apr 01; 55
AB  - 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 11C-IMA107 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.