Phosphodiesterase 10A PET radioligand development program: from pig to human

• Published in: The Journal of nuclear medicine (1978) Vol. 55; no. 4; p. 595
• Main Authors: Plisson, Christophe, Weinzimmer, David, Jakobsen, Steen, Natesan, Sridhar, Salinas, Cristian, Lin, Shu-Fei, Labaree, David, Zheng, Ming-Qiang, Nabulsi, Nabeel, Marques, Tiago Reis, Kapur, Shitij, Kawanishi, Eiji, Saijo, Takeaki, Gunn, Roger N, Carson, Richard E, Rabiner, Eugenii A
• Format: Journal Article
• Language: English
• Published: United States Society of Nuclear Medicine 01.04.2014
• Subjects: Animals; Biosynthesis; Brain; Brain - diagnostic imaging; Brain - metabolism; Cerebellum - diagnostic imaging; Cerebellum - metabolism; Comparative analysis; Dose-Response Relationship, Drug; Enzyme kinetics; Heterocyclic Compounds, 2-Ring - chemical synthesis; Heterocyclic Compounds, 2-Ring - pharmacokinetics; Hogs; Human subjects; Humans; Isotope Labeling - methods; Ligands; Papio; Phosphoric Diester Hydrolases - metabolism; Positron-Emission Tomography - methods; Quinoxalines - chemical synthesis; Quinoxalines - pharmacokinetics; Radiopharmaceuticals - chemical synthesis; Radiopharmaceuticals - pharmacokinetics; Swine; Tissue Distribution; in vivo; 11C; PDE10A; brain; PET
• ISSN: 0161-5505; 1535-5667; 1535-5667
• DOI: 10.2967/jnumed.113.131409

Four novel phosphodiesterase 10A (PDE10A) PET tracers have been synthesized, characterized in preclinical studies, and compared with the previously reported (11)C-MP-10. On the basis of in vitro data, IMA102, IMA104, IMA107, and IMA106 were identified as potential PDE10A radioligand candidates and labeled with either (11)C via N-methylation or with (18)F through an SN2 reaction, in the case of IMA102. These candidates were compared with (11)C-MP-10 in pilot in vivo studies in the pig brain. On the basis of these data, (11)C-IMA106 and (11)C-IMA107 were taken into further evaluation and comparison with (11)C-MP-10 in the primate brain. Finally, the most promising radioligand candidate was progressed into human evaluation. 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 (11)C-IMA107 and (11)C-MP-10 displayed the most favorable tissue kinetics and imaging properties. The administration of selective PDE10A inhibitors reduced the binding of (11)C-IMA107 and (11)C-MP-10 in the PDE10A-rich brain regions, in a dose-dependent manner. In the nonhuman primate brain, the tissue kinetics of (11)C-IMA107 and (11)C-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. (11)C-IMA107 was identified as the ligand with the highest binding potential while still possessing reversible kinetics. The first human administration of (11)C-IMA107 has demonstrated the expected regional distribution and suitably fast kinetics, indicating that (11)C-IMA107 will be a useful tool for the investigation of PDE10A status in the living human brain.