Steen Jakobsen

Phosphodiesterase 10A PET radioligand development program: from pig to human

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • Christophe Plisson
  • ,
  • David Weinzimmer
  • ,
  • Steen Jakobsen
  • Sridhar Natesan, Denmark
  • Cristian Salinas
  • ,
  • Shu-Fei Lin
  • ,
  • David Labaree
  • ,
  • Ming-Qiang Zheng, Denmark
  • Nabeel Nabulsi
  • ,
  • Tiago Reis Marques, Denmark
  • Shitij Kapur
  • ,
  • Eiji Kawanishi, Denmark
  • Takeaki Saijo, Denmark
  • Roger N Gunn
  • ,
  • Richard E Carson
  • ,
  • Eugenii A Rabiner

UNLABELLED: 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.

CONCLUSION: (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.

Original languageEnglish
JournalJournal of Nuclear Medicine
Pages (from-to)595-601
Number of pages7
Publication statusPublished - Apr 2014

    Research areas

  • Animals, Brain, Cerebellum, Dose-Response Relationship, Drug, Heterocyclic Compounds, 2-Ring, Humans, Isotope Labeling, Papio, Phosphoric Diester Hydrolases, Positron-Emission Tomography, Quinoxalines, Radiopharmaceuticals, Swine, Tissue Distribution

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