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.
Highlights
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
To determine the extent to which Compound 21 (C21) is suitable for activating DREADDs, we carried out a comprehensive series of studies in rodents and rhesus monkeys described in Supplementary Figs. 1 and 2
Our findings suggest that C21, like clozapine N-oxide (CNO), exhibits lower in vivo DREADD potency than clozapine and is not efficient in nonhuman primates (NHP) applications
Summary
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. [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. Designer receptors exclusively activated by designer drugs (DREADD)[1] technology is a powerful chemogenetic approach used for neuromodulation in uninstrumented research animals. We report the development of the first 18F-labeled high-affinity DREADD PET radioligand, [18F]JHU37107, which enables noninvasive and longitudinal DREADD detection and localization in locally targeted neurons and at long-range projection sites. Together, these new tools expand the power of DREADD chemogenetic technology to encompass translational applications for noninvasive manipulation and visualization of neuronal circuits
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