TY - JOUR T1 - Discovery and Development of <sup>11</sup>C-Lu AE92686 as a Radioligand for PET Imaging of Phosphodiesterase10A in the Brain JF - Journal of Nuclear Medicine JO - J Nucl Med SP - 1513 LP - 1518 DO - 10.2967/jnumed.114.140178 VL - 55 IS - 9 AU - Jan Kehler AU - John Paul Kilburn AU - Sergio Estrada AU - Søren Rahn Christensen AU - Anders Wall AU - Alf Thibblin AU - Mark Lubberink AU - Christoffer Bundgaard AU - Lise Tøttrup Brennum AU - Björn Steiniger-Brach AU - Claus Tornby Christoffersen AU - Stine Timmermann AU - Mads Kreilgaard AU - Gunnar Antoni AU - Benny Bang-Andersen AU - Jacob Nielsen Y1 - 2014/09/01 UR - http://jnm.snmjournals.org/content/55/9/1513.abstract N2 - Phosphodiesterase 10A (PDE10A) plays a key role in the regulation of brain striatal signaling, and several pharmaceutical companies currently investigate PDE10A inhibitors in clinical trials for various central nervous system diseases. A PDE10A PET ligand may provide evidence that a clinical drug candidate reaches and binds to the target. Here we describe the successful discovery and initial validation of the novel radiolabeled PDE10A ligand 5,8-dimethyl-2-[2-((1-11C-methyl)-4-phenyl-1H-imidazol-2-yl)-ethyl]-[1,2,4]triazolo[1,5-a]pyridine (11C-Lu AE92686) and its tritiated analog 3H-Lu AE92686. Methods: Initial in vitro experiments suggested Lu AE92686 as a promising radioligand, and the corresponding tritiated and 11C-labeled compounds were synthesized. 3H-Lu AE92686 was evaluated as a ligand for in vivo occupancy studies in mice and rats, and 11C-Lu AE92686 was evaluated as a PET tracer candidate in cynomolgus monkeys and in humans. Results: 11C-Lu AE92686 displayed high specificity and selectivity for PDE10A-expressing regions in the brain of cynomolgus monkeys and humans. Similar results were found in rodents using 3H-Lu AE92686. The binding of 11C-Lu AE92686 and 3H-Lu AE92686 to striatum was completely and dose-dependently blocked by the structurally different PDE10A inhibitor 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline (MP-10) in rodents and in monkeys. In all species, specific binding of the radioligand was seen in the striatum but not in the cerebellum, supporting the use of the cerebellum as a reference region. The binding potentials (BPND) of 11C-Lu AE92686 in the striatum of both cynomolgus monkeys and humans were evaluated by the simplified reference tissue model with the cerebellum as the reference tissue, and BPND was found to be high and reproducible—that is, BPNDs were 6.5 ± 0.3 (n = 3) and 7.5 ± 1.0 (n = 12) in monkeys and humans, respectively. Conclusion: Rodent, monkey, and human tests of labeled Lu AE92686 suggest that 11C-Lu AE92686 has great potential as a human PET tracer for the PDE10A enzyme. ER -