High-potency ligands for DREADD imaging and activation in rodents and monkeys

Jordi Bonaventura(National Institute on Drug Abuse), Mark A. G. Eldridge(National Institute of Mental Health), Feng Hu(Johns Hopkins University), Juan L. Gomez(National Institute on Drug Abuse), Marta Sánchez‐Soto(National Institute of Neurological Disorders and Stroke), Ara M. Abramyan(National Institute on Drug Abuse), Sherry Lam(National Institute on Drug Abuse), Matthew A. Boehm(National Institute on Drug Abuse), Christina M. Ruiz(University of California, Irvine), Mitchell R. Farrell(University of California, Irvine), Andrea Moreno(Aarhus University), Islam Faress(Aarhus University), Niels Andersen(Aarhus University), John Y. Lin(University of Tasmania), Ruin Moaddel(National Institute on Aging), Patrick J. Morris(National Center for Advancing Translational Sciences), Lei Shi(National Institute on Drug Abuse), David R. Sibley(National Institute of Neurological Disorders and Stroke), Stephen V. Mahler(University of California, Irvine), Sadegh Nabavi(Aarhus University), Martin G. Pomper(Johns Hopkins University), Antonello Bonci(National Institute on Drug Abuse), Andrew G. Horti(Johns Hopkins University), Barry J. Richmond(National Institute of Mental Health), Michael Michaelides(National Institute on Drug Abuse)
Nature Communications
October 11, 2019
10.1038/s41467-019-12236-z
Cited by 216Open Access
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Abstract

Abstract Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) are a popular chemogenetic technology for manipulation of neuronal activity in uninstrumented awake animals with potential for human applications as well. The prototypical DREADD agonist clozapine N- oxide (CNO) lacks brain entry and converts to clozapine, making it difficult to apply in basic and translational applications. Here we report the development of two novel DREADD agonists, JHU37152 and JHU37160, and the first dedicated 18 F positron emission tomography (PET) DREADD radiotracer, [ 18 F]JHU37107. We show that JHU37152 and JHU37160 exhibit high in vivo DREADD potency. [ 18 F]JHU37107 combined with PET allows for DREADD detection in locally-targeted neurons, and at their long-range projections, enabling noninvasive and longitudinal neuronal projection mapping.

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