Jan Kehler1, John Paul Kilburn1, Sergio Estrada2, Søren Rahn Christensen3, Anders Wall4, Alf Thibblin2, Mark Lubberink4, Christoffer Bundgaard1, Lise Tøttrup Brennum5, Björn Steiniger-Brach5, Claus Tornby Christoffersen6, Stine Timmermann7, Mads Kreilgaard8, Gunnar Antoni2, Benny Bang-Andersen9, Jacob Nielsen5. 1. Division of Discovery Chemistry and DMPK, H. Lundbeck A/S, Valby, Denmark. 2. Preclinical PET Platform, Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden. 3. Department of Clinical Pharmacology, H. Lundbeck A/S, Valby, Denmark. 4. Nuclear Medicine and PET, Uppsala University and Uppsala University Hospital, Uppsala, Sweden. 5. Division of Synaptic Transmission, H. Lundbeck A/S, Valby, Denmark. 6. Department of Molecular Pharmacology, H. Lundbeck A/S, Valby, Denmark. 7. Department of Quantitative Pharmacology, H. Lundbeck A/S, Valby, Denmark; and. 8. Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark. 9. Division of Discovery Chemistry and DMPK, H. Lundbeck A/S, Valby, Denmark Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark BAN@lundbeck.com.
Abstract
UNLABELLED: 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-(11)C-methyl)-4-phenyl-1H-imidazol-2-yl)-ethyl]-[1,2,4]triazolo[1,5-a]pyridine ((11)C-Lu AE92686) and its tritiated analog (3)H-Lu AE92686. METHODS: Initial in vitro experiments suggested Lu AE92686 as a promising radioligand, and the corresponding tritiated and (11)C-labeled compounds were synthesized. (3)H-Lu AE92686 was evaluated as a ligand for in vivo occupancy studies in mice and rats, and (11)C-Lu AE92686 was evaluated as a PET tracer candidate in cynomolgus monkeys and in humans. RESULTS: (11)C-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 (3)H-Lu AE92686. The binding of (11)C-Lu AE92686 and (3)H-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 (11)C-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 (11)C-Lu AE92686 has great potential as a human PET tracer for the PDE10A enzyme.
UNLABELLED: 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-(11)C-methyl)-4-phenyl-1H-imidazol-2-yl)-ethyl]-[1,2,4]triazolo[1,5-a]pyridine ((11)C-Lu AE92686) and its tritiated analog (3)H-Lu AE92686. METHODS: Initial in vitro experiments suggested Lu AE92686 as a promising radioligand, and the corresponding tritiated and (11)C-labeled compounds were synthesized. (3)H-Lu AE92686 was evaluated as a ligand for in vivo occupancy studies in mice and rats, and (11)C-Lu AE92686 was evaluated as a PET tracer candidate in cynomolgus monkeys and in humans. RESULTS:(11)C-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 (3)H-Lu AE92686. The binding of (11)C-Lu AE92686 and (3)H-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 (11)C-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 (11)C-Lu AE92686 has great potential as a human PET tracer for the PDE10A enzyme.
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