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

Jordi Bonaventura; Mark A G Eldridge; Feng Hu; Juan L Gomez; Marta Sanchez-Soto; Ara M Abramyan; Sherry Lam; Matthew A Boehm; Christina Ruiz; Mitchell R Farrell; Andrea Moreno; Islam Mustafa Galal Faress; Niels Andersen; John Y Lin; Ruin Moaddel; Patrick J Morris; Lei Shi; David R Sibley; Stephen V Mahler; Sadegh Nabavi; Martin G Pomper; Antonello Bonci; Andrew G Horti; Barry J Richmond; Michael Michaelides

doi:10.1038/s41467-019-12236-z

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

Nat Commun. 2019 Oct 11;10(1):4627. doi: 10.1038/s41467-019-12236-z.

Authors

Jordi Bonaventura¹, Mark A G Eldridge², Feng Hu³, Juan L Gomez¹, Marta Sanchez-Soto⁴, Ara M Abramyan⁵, Sherry Lam¹, Matthew A Boehm¹, Christina Ruiz⁶, Mitchell R Farrell⁶, Andrea Moreno⁷, Islam Mustafa Galal Faress⁷, Niels Andersen⁷, John Y Lin⁸, Ruin Moaddel⁹, Patrick J Morris¹⁰, Lei Shi⁵, David R Sibley⁴, Stephen V Mahler⁶, Sadegh Nabavi⁷, Martin G Pomper³, Antonello Bonci¹¹, Andrew G Horti¹², Barry J Richmond¹³, Michael Michaelides^{14

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Affiliations

¹ Biobehavioral Imaging and Molecular Neuropsychopharmacology Unit, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD, 21224, USA.
² Laboratory of Neuropsychology, National Institute of Mental Health Intramural Research Program, Bethesda, MD, 20892, USA.
³ Department of Radiology Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA.
⁴ Molecular Neuropharmacology Section, National Institute of Neurological Disorders and Stroke Intramural Research Program, Bethesda, MD, 20814, USA.
⁵ Computational Chemistry and Molecular Biophysics Unit, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD, 21224, USA.
⁶ Department of Neurobiology & Behavior, University of California, Irvine, CA, 92697, USA.
⁷ Department of Molecular Biology and Genetics, Dandrite, Aarhus University, 8000 Aarhus C, Aarhus, Denmark.
⁸ School of Medicine, College of Health and Medicine, University of Tasmania, Tasmania, TAS, 7000, Australia.
⁹ Laboratory of Clinical Investigation, National Institute on Aging Intramural Research Program, Baltimore, MD, 21224, USA.
¹⁰ National Center for Advancing Translational Sciences, Rockville, MD, 20850, USA.
¹¹ Synaptic Plasticity Section, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD, 21224, USA.
¹² Department of Radiology Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA. ahorti1@jhmi.edu.
¹³ Laboratory of Neuropsychology, National Institute of Mental Health Intramural Research Program, Bethesda, MD, 20892, USA. barryrichmond@mail.nih.gov.
¹⁴ Biobehavioral Imaging and Molecular Neuropsychopharmacology Unit, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD, 21224, USA. mike.michaelides@nih.gov.
¹⁵ Department of Psychiatry, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA. mike.michaelides@nih.gov.

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 ¹⁸F positron emission tomography (PET) DREADD radiotracer, [¹⁸F]JHU37107. We show that JHU37152 and JHU37160 exhibit high in vivo DREADD potency. [¹⁸F]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.

Publication types

Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Brain
Clozapine / analogs & derivatives
Clozapine / chemistry
Designer Drugs*
Fluorine Radioisotopes / analysis*
HEK293 Cells
Haplorhini
Humans
Ligands
Neuroanatomical Tract-Tracing Techniques / methods
Neuronal Tract-Tracers / analysis*
Neuronal Tract-Tracers / chemistry
Positron-Emission Tomography / methods
Rodentia

Substances

Designer Drugs
Fluorine Radioisotopes
Ligands
Neuronal Tract-Tracers
Clozapine
clozapine N-oxide

Abstract

Publication types

MeSH terms

Substances

Grants and funding