PT  - JOURNAL ARTICLE
AU  - Jordi Bonaventura
AU  - Mark A. Eldridge
AU  - Feng Hu
AU  - Juan L. Gomez
AU  - Marta Sanchez-Soto
AU  - Ara M. Abramyan
AU  - Sherry Lam
AU  - Matthew Boehm
AU  - Christina Ruiz
AU  - Mitchell Farrell
AU  - Andrea Moreno
AU  - Islam Mustafa Galal Faress
AU  - Niels Andersen
AU  - John Y. Lin
AU  - Ruin Moaddel
AU  - Patrick Morris
AU  - Lei Shi
AU  - David R. Sibley
AU  - Stephen V. Mahler
AU  - Sadegh Nabavi
AU  - Martin G. Pomper
AU  - Antonello Bonci
AU  - Andrew G. Horti
AU  - Barry J. Richmond
AU  - Michael Michaelides
TI  - Chemogenetic ligands for translational neurotheranostics
AID  - 10.1101/487637
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 487637
4099  - http://biorxiv.org/content/early/2018/12/07/487637.short
4100  - http://biorxiv.org/content/early/2018/12/07/487637.full
AB  - 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.