title: Further evaluation of [11C]MP-10 as a radiotracer for phosphodiesterase 10A: PET imaging study in rhesus monkeys and brain tissue metabolite analysis.
abstract: [(11)C]MP-10 is a potent and specific PET tracer previously shown to be suitable for imaging the phosphodiesterase 10A (PDE10A) in baboons with reversible kinetics and high specific binding. However, another report indicated that [(11)C]MP-10 displayed seemingly irreversible kinetics in rhesus monkeys, potentially due to the presence of a radiolabeled metabolite capable of penetrating the blood-brain-barrier (BBB) into the brain. This study was designed to address the discrepancies between the species by re-evaluating [(11)C]MP-10 in vivo in rhesus monkey with baseline scans to assess tissue uptake kinetics and self-blocking scans with unlabeled MP-10 to determine binding specificity. Ex vivo studies with one rhesus monkey and 4 Sprague-Dawley rats were also performed to investigate the presence of radiolabeled metabolites in the brain. Our results indicated that [(11)C]MP-10 displayed reversible uptake kinetics in rhesus monkeys, albeit slower than in baboons. Administration of unlabeled MP-10 reduced the binding of [(11)C]MP-10 in a dose-dependent manner in all brain regions including the cerebellum. Consequently, the cerebellum appeared not to be a suitable reference tissue in rhesus monkeys. Regional volume of distribution (VT) was mostly reliably derived with the multilinear analysis (MA1) method. In ex vivo studies in the monkey and rats only negligible amount of radiometabolites was seen in the brain of either species. In summary, results from the present study strongly support the suitability of [(11)C]MP-10 as a radiotracer for PET imaging and quantification of PDE10A in nonhuman primates.
authors.affiliation: Department of Diagnostic Radiology, PET Center, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Shu-Fei
authors.initials: SF
authors.lastname: Lin
authors.forename: David
authors.initials: D
authors.lastname: Labaree
authors.forename: Ming-Kai
authors.initials: MK
authors.lastname: Chen
authors.forename: Daniel
authors.initials: D
authors.lastname: Holden
authors.forename: Jean-Dominique
authors.initials: JD
authors.lastname: Gallezot
authors.forename: Michael
authors.initials: M
authors.lastname: Kapinos
authors.forename: Jo-Ku
authors.initials: JK
authors.lastname: Teng
authors.forename: Soheila
authors.initials: S
authors.lastname: Najafzadeh
authors.forename: Christophe
authors.initials: C
authors.lastname: Plisson
authors.forename: Eugenii A
authors.initials: EA
authors.lastname: Rabiner
authors.forename: Roger N
authors.initials: RN
authors.lastname: Gunn
authors.forename: Richard E
authors.initials: RE
authors.lastname: Carson
authors.forename: Yiyun
authors.initials: Y
authors.lastname: Huang
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging*; D008253:Macaca mulatta; D008297:Male; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D049268:Positron-Emission Tomography; D011720:Pyrazoles / Q000493:pharmacokinetics*; D011804:Quinolines / Q000493:pharmacokinetics*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
chemical_list: C545121:2-((4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)phenoxy)methyl)quinoline; D011720:Pyrazoles; D011804:Quinolines; D019275:Radiopharmaceuticals; D010727:Phosphoric Diester Hydrolases
keywords: PDE10A; PET; [11C]MP-10; brain; radiometabolite