title: Phosphodiesterase 10A PET radioligand development program: from pig to human.
abstract: Four novel phosphodiesterase 10A (PDE10A) PET tracers have been synthesized, characterized in preclinical studies, and compared with the previously reported (11)C-MP-10.
  
  
  METHODS
  On the basis of in vitro data, IMA102, IMA104, IMA107, and IMA106 were identified as potential PDE10A radioligand candidates and labeled with either (11)C via N-methylation or with (18)F through an SN2 reaction, in the case of IMA102. These candidates were compared with (11)C-MP-10 in pilot in vivo studies in the pig brain. On the basis of these data, (11)C-IMA106 and (11)C-IMA107 were taken into further evaluation and comparison with (11)C-MP-10 in the primate brain. Finally, the most promising radioligand candidate was progressed into human evaluation.
  
  
  RESULTS
  All 5 tracers were produced with good radiochemical yield and specific activity. All candidates readily entered the brain and demonstrated a heterogeneous distribution consistent with the known expression of PDE10A. Baseline PET studies in the pig and baboon showed that (11)C-IMA107 and (11)C-MP-10 displayed the most favorable tissue kinetics and imaging properties. The administration of selective PDE10A inhibitors reduced the binding of (11)C-IMA107 and (11)C-MP-10 in the PDE10A-rich brain regions, in a dose-dependent manner. In the nonhuman primate brain, the tissue kinetics of (11)C-IMA107 and (11)C-MP-10 were well described by a 2-tissue-compartment model, allowing robust estimates of the regional total volume of distribution. Blockade with unlabeled MP-10 confirmed the suitability of the cerebellum as a reference tissue and enabled the estimation of regional binding potential as the outcome measure of specific binding.
  
  
  CONCLUSIONS
  (11)C-IMA107 was identified as the ligand with the highest binding potential while still possessing reversible kinetics. The first human administration of (11)C-IMA107 has demonstrated the expected regional distribution and suitably fast kinetics, indicating that (11)C-IMA107 will be a useful tool for the investigation of PDE10A status in the living human brain.
authors.affiliation: Imanova Ltd., Centre for Imaging Sciences, Hammersmith Hospital, London, United Kingdom.
authors.forename: Christophe
authors.initials: C
authors.lastname: Plisson
authors.forename: David
authors.initials: D
authors.lastname: Weinzimmer
authors.forename: Steen
authors.initials: S
authors.lastname: Jakobsen
authors.forename: Sridhar
authors.initials: S
authors.lastname: Natesan
authors.forename: Cristian
authors.initials: C
authors.lastname: Salinas
authors.forename: Shu-Fei
authors.initials: SF
authors.lastname: Lin
authors.forename: David
authors.initials: D
authors.lastname: Labaree
authors.forename: Ming-Qiang
authors.initials: MQ
authors.lastname: Zheng
authors.forename: Nabeel
authors.initials: N
authors.lastname: Nabulsi
authors.forename: Tiago Reis
authors.initials: TR
authors.lastname: Marques
authors.forename: Shitij
authors.initials: S
authors.lastname: Kapur
authors.forename: Eiji
authors.initials: E
authors.lastname: Kawanishi
authors.forename: Takeaki
authors.initials: T
authors.lastname: Saijo
authors.forename: Roger N
authors.initials: RN
authors.lastname: Gunn
authors.forename: Richard E
authors.initials: RE
authors.lastname: Carson
authors.forename: Eugenii A
authors.initials: EA
authors.lastname: Rabiner
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D002531:Cerebellum / Q000000981:diagnostic imaging / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006574:Heterocyclic Compounds, 2-Ring / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D006801:Humans; D007553:Isotope Labeling / Q000379:methods; D010215:Papio; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D049268:Positron-Emission Tomography / Q000379:methods*; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D013552:Swine; D014018:Tissue Distribution
chemical_list: D006574:Heterocyclic Compounds, 2-Ring; C000588665:IMA107; D011810:Quinoxalines; D019275:Radiopharmaceuticals; C119843:PDE10A protein, human; D010727:Phosphoric Diester Hydrolases
keywords: 11C; PDE10A; PET; brain; in vivo