RT Journal Article
SR Electronic
T1 Phosphodiesterase 10A PET Radioligand Development Program: From Pig to Human
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 595
OP 601
DO 10.2967/jnumed.113.131409
VO 55
IS 4
A1 Plisson, Christophe
A1 Weinzimmer, David
A1 Jakobsen, Steen
A1 Natesan, Sridhar
A1 Salinas, Cristian
A1 Lin, Shu-Fei
A1 Labaree, David
A1 Zheng, Ming-Qiang
A1 Nabulsi, Nabeel
A1 Marques, Tiago Reis
A1 Kapur, Shitij
A1 Kawanishi, Eiji
A1 Saijo, Takeaki
A1 Gunn, Roger N.
A1 Carson, Richard E.
A1 Rabiner, Eugenii A.
YR 2014
UL http://jnm.snmjournals.org/content/55/4/595.abstract
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.