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

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  • Jordi Bonaventura, National Institutes of Health
  • ,
  • Mark A.G. Eldridge, National Institutes of Health
  • ,
  • Feng Hu, Johns Hopkins University
  • ,
  • Juan L. Gomez, National Institutes of Health
  • ,
  • Marta Sanchez-Soto, National Institutes of Health
  • ,
  • Ara M. Abramyan, National Institutes of Health
  • ,
  • Sherry Lam, National Institutes of Health
  • ,
  • Matthew A. Boehm, National Institutes of Health
  • ,
  • Christina Ruiz, University of California at Irvine
  • ,
  • Mitchell R. Farrell, University of California at Irvine
  • ,
  • Andrea Moreno
  • Islam Mustafa Galal Faress
  • Niels Andersen
  • John Y. Lin, University of Tasmania
  • ,
  • Ruin Moaddel, National Institute on Aging
  • ,
  • Patrick J. Morris, National Institutes of Health
  • ,
  • Lei Shi, National Institutes of Health
  • ,
  • David R. Sibley, National Institutes of Health
  • ,
  • Stephen V. Mahler, University of California at Irvine
  • ,
  • Sadegh Nabavi
  • Martin G. Pomper, Johns Hopkins University
  • ,
  • Antonello Bonci, National Institutes of Health
  • ,
  • Andrew G. Horti, Johns Hopkins University
  • ,
  • Barry J. Richmond, National Institutes of Health
  • ,
  • Michael Michaelides, National Institutes of Health, Johns Hopkins University

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.

Original languageEnglish
Article number4627
JournalNature Communications
Volume10
Issue1
Number of pages12
ISSN2041-1723
DOIs
Publication statusPublished - 1 Dec 2019

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