Chemogenetic ligands for translational neurotheranostics

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

Research output: Contribution to journalArticlepeer-review

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 precision medicine-based clinical theranostics. DREADD ligands developed to date are not appropriate for such translational applications. The prototypical DREADD agonist clozapine N-oxide (CNO) lacks brain entry and converts to clozapine. The second-generation DREADD agonist, Compound 21 (C21), was developed to overcome these limitations. We found that C21 has low brain penetrance, weak affinity, and low in vivo DREADD occupancy. To address these drawbacks, we developed two new DREADD agonists, JHU37152 and JHU37160, and the first dedicated positron emission tomography (PET) DREADD radiotracer, [18F]JHU37107. 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 for the first time, noninvasive and longitudinal neuronal projection mapping and potential for neurotheranostic applications.

Original languageEnglish (US)
JournalUnknown Journal
DOIs
StatePublished - Dec 7 2018

Keywords

  • DREADDs
  • hM3Dq
  • hM4Di
  • JHU37107
  • JHU37160
  • JHU57152

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • Immunology and Microbiology(all)
  • Neuroscience(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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