量研学術機関リポジトリ「QST-Repository」は、国立研究開発法人 量子科学技術研究開発機構に所属する職員等が生み出した学術成果（学会誌発表論文、学会発表、研究開発報告書、特許等）を集積しインターネット上で広く公開するサービスです。 Welcome to QST-Repository where we accumulates and discloses the academic research results(Journal Publications, Conference presentation, Research and Development Report, Patent, etc.) of the members of National Institutes for Quantum and Radiological Science and Technology.
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The chemogenetic technology, Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) offers a means to temporally and remotely control activity of a target cell population expressing a "designer receptor" by systemic delivery of an agonist compound. Non-invasive visualization of the inhibitory designer receptor, hM4Di, by positron emission tomography (PET) (Nagai et al., 2016) now enables us to monitor the expression and the agonist dose–occupancy relationship that provides the critical information for successful chemogenetic silencing in long-term studies in monkeys as well as for future clinical therapeutics. However, the current PET ligand, 11C-clozapine, has low specificity for DREADDs, thereby the image suffers from a regional difference in "baseline noise". Here we developed a new ligand, a carbon-11-labeled derivative of DREADD agonists (Chen et al., 2015), to improve the sensitivity of DREADD-PET imaging. In vitro assay demonstrated that, unlike clozapine, the derivative did not display high potency for major endogenous G protein coupled receptors. We examined the new PET ligand in a monkey that received injections of an hM4Di-expressing viral vector into the unilateral putamen. As seen with 11C-clozapine, PET imaging localized an increased uptake of the new ligand at the putative hM4Di-expressing site. Compared with 11C-clozapine, the signal-to-noise ratio was largely improved; the ligand uptake at the putative hM4Di-expressing site was enhanced by about 10%, while the baseline uptakes in the striatum or other subcortical areas were reduced by about 30%. Pretreatment with an unlabeled ligand at a dose of 1 mg/kg almost completely diminished the uptake at the injection site, and therefore the ligand uptake appeared to reflect in vivo DREADD expression. Besides the injection site in the putamen, an increased uptake was also found in its projection areas, i.e., the globus pallidus and the substantia nigra, presumably reflecting hM4Di expression at the axon terminal. Two additional monkeys were scanned following bilateral injections of an AAV-hM4Di vector into the rostromedial caudate or the thalamus. In vivo hM4Di expressions in these two subcortical areas were also detected as high ligand uptakes. These results indicate that our new PET ligand provides a high DREADD selectivity in subcortical regions in monkeys, thus being beneficial for quantitative assessment and sensitive detection of DREADD expression even at the axon terminal.
A novel PET ligand for visualising cellular and axonal DREADD expression in monkeys
