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J Nucl Med. 2014 Apr;55(4):595-601. doi: 10.2967/jnumed.113.131409. Epub 2014 Mar 10.

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

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1
Imanova Ltd., Centre for Imaging Sciences, Hammersmith Hospital, London, United Kingdom.

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.

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.

KEYWORDS:

11C; PDE10A; PET; brain; in vivo

PMID:
24614221
DOI:
10.2967/jnumed.113.131409
[Indexed for MEDLINE]
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