title: Synthesis and biological evaluation of carbon-11 and fluorine-18 labeled tracers for in vivo visualization of PDE10A.
abstract: BACKGROUND
  In vivo visualization of PDE10A using PET provides a tool to evaluate the role of PDE10A in various neuropsychiatric diseases and can also be useful in the clinical evaluation of PDE10A inhibitor drug candidates. We evaluated several carbon-11 and fluorine-18 labeled PDE10A inhibitors as potential PDE10A PET radioligands.
  
  
  METHODS
  [(11)C]MP10, [(11)C]JNJ42071965 and four other tracers were developed. Their biodistribution was evaluated in rats. Rat plasma and brain radiometabolites were quantified. Baseline microPET imaging was performed in normal rats and PDE10A knockout (KO) and wild-type (WT) mice. Blocking and displacement studies were conducted. The selectivity of the tracer binding was further studied in an ex vivo autoradiography experiment in PDE10A KO and WT mice.
  
  
  RESULTS
  Biodistribution showed brain uptake for all tracers in the striatum and wash-out from the cerebellum. [(11)C]1 ((11)C-MP10) had the highest specific uptake index (striatum (S) vs. cerebellum (C) ratios (S/C)-1) at 60 min (7.4). [(11)C]5 ([(11)C]JNJ42071965) had a high index at the early time points (1.0 and 3.7 at 2 and 30 min p.i., respectively). The affinity of [(11)C]4, [(18)F]3 and [(18)F]6 was too low to visualize PDE10A using microPET. [(11)C] 2 showed a specific binding, while kinetics of [(11)C]1 were too slow. [(11)C]5 reached equilibrium after 10 min (uptake index=1.2). Blocking and displacement experiments in rats and baseline imaging in PDE10A KO mice showed specific and reversible binding of [(11)C]5 to PDE10A.
  
  
  CONCLUSIONS
  We successfully radiolabeled and evaluated six radiotracers for their potential to visualize PDE10A in vivo. While [(11)C]1 had the highest striatal specific uptake index, its slow kinetics likely compromise clinical use of this tracer. [(11)C]5 has a relatively high striatum-to-background ratio and fast kinetic profile, which makes it a valuable carbon-11 alternative.
authors.affiliation: Laboratory for Radiopharmacy, KU Leuven, Belgium; MoSAIC, Molecular Small Animal Imaging Centre, KU Leuven, Belgium.
authors.forename: Maarten
authors.initials: M
authors.lastname: Ooms
authors.affiliation: Laboratory for Radiopharmacy, KU Leuven, Belgium; MoSAIC, Molecular Small Animal Imaging Centre, KU Leuven, Belgium.
authors.forename: Sofie
authors.initials: S
authors.lastname: Celen
authors.affiliation: Department of Nuclear Medicine & Molecular Imaging, University Medical Center Groningen, The Netherlands.
authors.forename: Michel
authors.initials: M
authors.lastname: Koole
authors.affiliation: Janssen Research & Development, Beerse, Belgium.
authors.forename: Xavier
authors.initials: X
authors.lastname: Langlois
authors.affiliation: Janssen Research & Development, Beerse, Belgium.
authors.forename: Mark
authors.initials: M
authors.lastname: Schmidt
authors.affiliation: Janssen Research & Development, Toledo, Spain.
authors.forename: Meri
authors.initials: M
authors.lastname: De Angelis
authors.affiliation: Janssen Research & Development, Toledo, Spain.
authors.forename: José Ignacio
authors.initials: JI
authors.lastname: Andrés
authors.affiliation: Laboratory for Radiopharmacy, KU Leuven, Belgium; MoSAIC, Molecular Small Animal Imaging Centre, KU Leuven, Belgium.
authors.forename: Alfons
authors.initials: A
authors.lastname: Verbruggen
authors.affiliation: MoSAIC, Molecular Small Animal Imaging Centre, KU Leuven, Belgium; Division of Nuclear Medicine, KU Leuven and University Hospital Leuven, Belgium.
authors.forename: Koen
authors.initials: K
authors.lastname: Van Laere
authors.affiliation: Laboratory for Radiopharmacy, KU Leuven, Belgium; MoSAIC, Molecular Small Animal Imaging Centre, KU Leuven, Belgium. Electronic address: guy.bormans@pharm.kuleuven.be.
authors.forename: Guy
authors.initials: G
authors.lastname: Bormans
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D002250:Carbon Radioisotopes; D060326:Chemistry Techniques, Synthetic; D004791:Enzyme Inhibitors / Q000097:blood / Q000138:chemical synthesis* / Q000378:metabolism; D005462:Fluorine Radioisotopes; D055786:Gene Knockout Techniques; D008297:Male; D051379:Mice; D010727:Phosphoric Diester Hydrolases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D049268:Positron-Emission Tomography / Q000379:methods*; D011849:Radioactive Tracers; D011854:Radiochemistry; D051381:Rats
chemical_list: D002250:Carbon Radioisotopes; D004791:Enzyme Inhibitors; D005462:Fluorine Radioisotopes; D011849:Radioactive Tracers; C492284:Pde10a protein, mouse; D010727:Phosphoric Diester Hydrolases
keywords: (18)F; 11C; CNS imaging; PDE10A; Positron emission tomography