Radiosynthesis and in vivo evaluation of [ 11C]MP-10 as a positron emission tomography radioligand for phosphodiesterase 10A

• Published in: Nuclear medicine and biology Vol. 38; no. 6; pp. 875 - 884
• Main Authors: Plisson, Christophe, Salinas, Cristian, Weinzimmer, David, Labaree, David, Lin, Shu-Fei, Ding, Yu-Shin, Jakobsen, Steen, Smith, Paul W., Eiji, Kawanishi, Carson, Richard E., Gunn, Roger N., Rabiner, Eugenii A.
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.08.2011; Elsevier
• Subjects: Animals; Biological and medical sciences; Brain; Carbon Radioisotopes; Carbon-11; Contrast media. Radiopharmaceuticals; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - metabolism; Female; Humans; In vivo; Kinetics; Ligands; Medical sciences; MP-10; Papio; PDE10A; PET; Pharmacology. Drug treatments; Phosphoric Diester Hydrolases - metabolism; Positron-Emission Tomography - methods; Pyrazoles - chemical synthesis; Pyrazoles - metabolism; Quinolines - chemical synthesis; Quinolines - metabolism; Radiochemistry - methods; Radiology; Substrate Specificity; Swine; In vivo; Brain; PDE10A; MP-10; Carbon-11; PET; Radionuclide study; Nuclear medicine; Central nervous system; Monkey; Esterases; Phosphoric diester hydrolases; Encephalon; Primates; Radioisotopic product; Chemical synthesis; Ungulata; Biomedical engineering; 3',5'-Cyclic-nucleotide phosphodiesterase; Radiolabelling; Enzyme; Enzyme inhibitor; Pig; Vertebrata; Mammalia; Animal; Hydrolases; Artiodactyla; Positron emission tomography; Emission tomography
• ISSN: 0969-8051; 1872-9614
• DOI: 10.1016/j.nucmedbio.2011.02.005

The aim of this study was to evaluate a newly reported positron emission tomography (PET) radioligand [ 11C]MP-10, a potent and selective inhibitor of the central phosphodiesterase 10A enzyme (PDE10A) in vivo, using PET. A procedure was developed for labeling MP-10 with carbon-11. [ 11C]MP-10 was evaluated in vivo both in the pig and baboon brain. Alkylation of the corresponding desmethyl compound with [ 11C]methyl iodide produced [ 11C]MP-10 with good radiochemical yield and specific activity. PET studies in the pig showed that [ 11C]MP-10 rapidly entered the brain reaching peak tissue concentration at 1–2 min postadministration, followed by washout from the tissue. Administration of a selective PDE10A inhibitor reduced the binding in all brain regions to the levels of the cerebellum, demonstrating the saturability and selectivity of [ 11C]MP-10 binding. In the nonhuman primate, the brain tissue kinetics of [ 11C]MP-10 were slower, reaching peak tissue concentrations at 30–60 min postadministration. In both species, the observed rank order of regional brain signal was striatum>diencephalon>cortical regions=cerebellum, consistent with the known distribution and concentration of PDE10A. [ 11C]MP-10 brain kinetics were well described by a two-tissue compartment model, and estimates of total volume of distribution ( V T) were obtained. Blocking studies with unlabeled MP-10 revealed the suitability of the cerebellum as a reference tissue and enabled the estimation of regional binding potential ( BP ND) as the outcome measure of specific binding. Quantification of [ 11C]MP-10 binding using the simplified reference tissue model with cerebellar input function produced BP ND estimates consistent with those obtained by the two-tissue compartment model. We demonstrated that [ 11C]MP-10 possesses good characteristics for the in vivo quantification of the PDE10A in the brain by PET.