title: Preclinical evaluation of 18F-JNJ41510417 as a radioligand for PET imaging of phosphodiesterase-10A in the brain.
abstract: Phosphodiesterases are enzymes that inactivate the intracellular second messengers 3',5'-cyclic adenosine-monophosphate and/or cyclic guanosine-monophosphate. Of all 11 known phosphodiesterase families, phosphodiesterase-10A (PDE10A) has the most restricted distribution, with high expression in the striatum. PDE10A inhibitors are pursued as drugs for treatment of neuropsychiatric disorders. We have synthesized and evaluated (18)F-JNJ41510417 as a selective and high-affinity radioligand for in vivo brain imaging of PDE10A using PET.
  
  
  METHODS
  The biodistribution of (18)F-JNJ41510417 was evaluated in rats. Rat plasma and perfused brain homogenates were analyzed by high-performance liquid chromatography to quantify radiometabolites. Dynamic small-animal PET was performed in rats and in wild-type and PDE10A knock-out mice and compared with ex vivo autoradiography. Blocking and displacement experiments were performed using the nonradioactive analog and other selective PDE10A inhibitors.
  
  
  RESULTS
  Tissue distribution studies showed predominant hepatobiliary excretion, sufficient brain uptake (0.56 ± 0.00 percentage injected dose at 2 min after tracer injection), and continuous accumulation of the tracer in the striatum over time; rapid washout of nonspecific binding from other brain regions was observed. Polar radiometabolites were detected in plasma and brain tissue. Dynamic small-animal PET showed continuous tracer accumulation in the striatum, with rapid decline in the cortex and cerebellum. Pretreatment and chase experiments with PDE10A inhibitors showed that the tracer binding to PDE10A was specific and reversible. Imaging in PDE10A knock-out and wild-type mice further confirmed that binding in the striatum was specific for PDE10A.
  
  
  CONCLUSIONS
  Experiments in rats and PDE10A knock-out mice indicate that (18)F-JNJ41510417 binds specifically and reversibly to PDE10A in the striatum, suggesting that this new fluorinated quinoline derivative is a promising candidate for in vivo imaging of PDE10A using PET.
authors.affiliation: Laboratory for Radiopharmacy, Faculty of Pharmaceutical Sciences, K.U. Leuven, Leuven, Belgium.
authors.forename: Sofie
authors.initials: S
authors.lastname: Celen
authors.forename: Michel
authors.initials: M
authors.lastname: Koole
authors.forename: Meri
authors.initials: M
authors.lastname: De Angelis
authors.forename: Ivan
authors.initials: I
authors.lastname: Sannen
authors.forename: Satish K
authors.initials: SK
authors.lastname: Chitneni
authors.forename: Jesus
authors.initials: J
authors.lastname: Alcazar
authors.forename: Stefanie
authors.initials: S
authors.lastname: Dedeurwaerdere
authors.forename: Dieder
authors.initials: D
authors.lastname: Moechars
authors.forename: Mark
authors.initials: M
authors.lastname: Schmidt
authors.forename: Alfons
authors.initials: A
authors.lastname: Verbruggen
authors.forename: Xavier
authors.initials: X
authors.lastname: Langlois
authors.forename: Koen
authors.initials: K
authors.lastname: Van Laere
authors.forename: José Ignacio
authors.initials: JI
authors.lastname: Andrés
authors.forename: Guy
authors.initials: G
authors.lastname: Bormans
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical; D008657:Metabolic Clearance Rate; D051379:Mice; D009928:Organ Specificity; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D049268:Positron-Emission Tomography / Q000379:methods*; D011720:Pyrazoles / Q000493:pharmacokinetics*; D011804:Quinolines / Q000493:pharmacokinetics*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D051381:Rats; D014018:Tissue Distribution
chemical_list: C553449:JNJ41510417; D011720:Pyrazoles; D011804:Quinolines; D019275:Radiopharmaceuticals; C492284:Pde10a protein, mouse; D010727:Phosphoric Diester Hydrolases