量子科学技術研究開発機構学術機関リポジトリ

Objectives: Designer Receptors Exclusively Activated by Designer Drug (DREADDs) is one of the chemogenetic technologies that afford to selectively and remotely control the activity of neuronal population expressing “designer receptor” by systemic delivery of the biologically inert compound. Muscarinic-based designer receptors, hM3Dq (excitatory) and hM4Di (inhibitory), can be activated by clozapine-N-oxide (CNO), are most widely used. DREADDs can be applicable for larger and discontinuous brain tissues, which non-human primate studies demand. For the application of DREADD to monkey study, it is desirable to monitor the DREADD expression in vivo. In addition, CNO has modest brain permeability and can be metabolized to clozapine, which is also a potent DREADD agonist. Since clozapine possesses activity at sites for numerous endogenous receptors, the CNO administration could be associated with off-target actions. In this study, we demonstrated that a novel ligand, deschloroclozapine (DCZ), served a dual purpose in chemogenetics: (1) as a selective compound for visualization of DREADD expression in vivo by positron emission tomography (PET) imaging and (2) as a selective agonist for muscarinic-based DREADDs.
Methods and Results: In vitro inhibition binding assay with 3H-QNB revealed that DCZ is a high DREADD selective ligand; it exhibited high affinity to hM3Dq and hM4Di (6.3 and 4.2 nM, respectively: comparable to clozapine and 100-fold stronger than CNO), while it had moderate or low affinities (>50 nM) for a large number of endogenous receptors. It was confirmed by 11C-DCZ with PET in monkeys; significant uptake of 11C-DCZ was specifically found in DREADD expressing regions, while uptakes in non-DREADD expression regions were small. Agonist efficacy of DCZ was examined by electrophysiological recording in a monkey received a hM3Dq-vector injection. After systemic DCZ administration, but not a vehicle, neuronal activity in the hM3Dq-positive area was rapidly and significantly increased, whereas the activity in the area outside hM3Dq-positive sites did not change. A pharmacokinetic study revealed that any major significant metabolites of DCZ were not detected in the plasma and CSF after DCZ administration.
Conclusions: These results indicate that (1) 11C-DCZ is a suitable and sensitive PET ligand for visualization of DREADD expression and (2) DCZ is a metabolically stable, extremely potent, highly brain-penetrable, and selective agonist for DREADDs, the combination of which provides clear benefits for non-human primates chemogenetics and future therapeutic applications.

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BrainPET2019

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2019-07-05

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2023-05-15 18:44:34.107821

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A novel ligand “deschloroclozapine” selectively visualizes and activates chemogenetic receptors in non-human primates

× Nagai, Yuji

× Miyakawa, Naohisa

× Takuwa, Hiroyuki

× Hori, Yukiko

× Oyama, Kei

× Ji, Bin

× Manami, Takahashi

× Xi-Ping, Haung

× T. Slocum, Samuel

× Xiong, Yan

× Hirabayashi, Toshiyuki

× Fujimoto, Atsushi

× Mimura, Koki

× G. English, Justin

× Liu, Jing

× Ken-ichi, Inoue

× Kumata, Katsushi

× Seki, Chie

× Ono, Maiko

× Shimojo, Masafumi

× Ming-Rong, Zhang

× Tomita, Yutaka

× Suhara, Tetsuya

× Takada, Masahiko

× Higuchi, Makoto

× Jin, Jian

× L. Roth, Bryan

× Minamimoto, Takafumi