title: Discovery and development of 11C-Lu AE92686 as a radioligand for PET imaging of phosphodiesterase10A in the brain.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Discovery Chemistry and DMPK, H. Lundbeck A/S, Valby, Denmark.
authors.forename: Jan
authors.initials: J
authors.lastname: Kehler
authors.affiliation: Division of Discovery Chemistry and DMPK, H. Lundbeck A/S, Valby, Denmark.
authors.forename: John Paul
authors.initials: JP
authors.lastname: Kilburn
authors.affiliation: Preclinical PET Platform, Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden.
authors.forename: Sergio
authors.initials: S
authors.lastname: Estrada
authors.affiliation: Department of Clinical Pharmacology, H. Lundbeck A/S, Valby, Denmark.
authors.forename: Søren Rahn
authors.initials: SR
authors.lastname: Christensen
authors.affiliation: Nuclear Medicine and PET, Uppsala University and Uppsala University Hospital, Uppsala, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Wall
authors.affiliation: Preclinical PET Platform, Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden.
authors.forename: Alf
authors.initials: A
authors.lastname: Thibblin
authors.affiliation: Nuclear Medicine and PET, Uppsala University and Uppsala University Hospital, Uppsala, Sweden.
authors.forename: Mark
authors.initials: M
authors.lastname: Lubberink
authors.affiliation: Division of Discovery Chemistry and DMPK, H. Lundbeck A/S, Valby, Denmark.
authors.forename: Christoffer
authors.initials: C
authors.lastname: Bundgaard
authors.affiliation: Division of Synaptic Transmission, H. Lundbeck A/S, Valby, Denmark.
authors.forename: Lise Tøttrup
authors.initials: LT
authors.lastname: Brennum
authors.affiliation: Division of Synaptic Transmission, H. Lundbeck A/S, Valby, Denmark.
authors.forename: Björn
authors.initials: B
authors.lastname: Steiniger-Brach
authors.affiliation: Department of Molecular Pharmacology, H. Lundbeck A/S, Valby, Denmark.
authors.forename: Claus Tornby
authors.initials: CT
authors.lastname: Christoffersen
authors.affiliation: Department of Quantitative Pharmacology, H. Lundbeck A/S, Valby, Denmark; and.
authors.forename: Stine
authors.initials: S
authors.lastname: Timmermann
authors.affiliation: Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Mads
authors.initials: M
authors.lastname: Kreilgaard
authors.affiliation: Preclinical PET Platform, Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Antoni
authors.affiliation: 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.
authors.forename: Benny
authors.initials: B
authors.lastname: Bang-Andersen
authors.affiliation: Division of Synaptic Transmission, H. Lundbeck A/S, Valby, Denmark.
authors.forename: Jacob
authors.initials: J
authors.lastname: Nielsen
mesh_terms: D000328:Adult; D005260:Female; D006801:Humans; D008297:Male; D051381:Rats; D001921:Brain / Q000201:enzymology; D002250:Carbon Radioisotopes; D002851:Chromatography, High Pressure Liquid; D008024:Ligands; D008252:Macaca fascicularis; D010726:Phosphodiesterase Inhibitors; D010727:Phosphoric Diester Hydrolases / Q000032:analysis; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals; D017207:Rats, Sprague-Dawley; D000818:Animals
chemical_list: D002250:Carbon Radioisotopes; D008024:Ligands; C119843:PDE10A protein, human; D010726:Phosphodiesterase Inhibitors; D010727:Phosphoric Diester Hydrolases; D019275:Radiopharmaceuticals
keywords: 11C; 3H; Lu AE92686; PDE10A; PET; brain imaging