Chemogenetic ligands for translational neurotheranostics

Jordi Bonaventura; Mark A. G. Eldridge; Feng Hu; Juan L. Gomez; Marta Sánchez‐Soto; Ara M. Abramyan; Sherry Lam; Matthew A. Boehm; Christina M. 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:10.1101/487637

NeurosciencebioRxivDec 7, 2018

Preprint

Chemogenetic ligands for translational neurotheranostics

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

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.

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