Chronic behavioral manipulation via orally delivered chemogenetic actuator in macaques

The chemogenetic technology referred to as designer receptors exclusively activated by designer drugs (DREADDs) offers reversible means to control neuronal activity for investigating its functional correlation with behavioral action. Deschloroclozapine (DCZ), a recently-developed highly potent and selective DREADDs actuator, displays a capacity to expand the utility of DREADDs for chronic manipulation without side-effects in nonhuman primates, which has not yet been validated. Here we investigated the pharmacokinetics and behavioral effects of orally administered DCZ in macaque monkeys. Pharmacokinetic analysis and positron emission tomography (PET) occupancy examination demonstrated that oral administration of DCZ yielded slower and prolonged kinetics, and that its bioavailability was 10-20% of that in the case of systemic injection. Oral DCZ (300-1000 μg/kg) induced significant working memory impairments for at least 4 h in monkeys with hM4Di expressed in the prefrontal cortex. Repeated daily oral doses of DCZ consistently caused similar impairments over two weeks without discernible desensitization. Our results indicate that orally delivered DCZ affords a less invasive strategy for chronic but reversible chemogenetic manipulation of neuronal activity in nonhuman primates, and this has potential for clinical application.

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

Nature Communications ◽

10.1038/s41467-019-12236-z ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 20

Author(s):

Jordi Bonaventura ◽

Mark A. G. Eldridge ◽

Feng Hu ◽

Juan L. Gomez ◽

Marta Sanchez-Soto ◽

...

Keyword(s):

Positron Emission Tomography ◽

Long Range ◽

Neuronal Activity ◽

Designer Drugs ◽

Emission Tomography ◽

High Potency ◽

Projection Mapping ◽

Positron Emission ◽

Neuronal Projection

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.

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Chemogenetic ligands for translational neurotheranostics

10.1101/487637 ◽

2018 ◽

Cited By ~ 1

Author(s):

Jordi Bonaventura ◽

Mark A. Eldridge ◽

Feng Hu ◽

Juan L. Gomez ◽

Marta Sanchez-Soto ◽

...

Keyword(s):

Positron Emission Tomography ◽

Neuronal Activity ◽

Designer Drugs ◽

Emission Tomography ◽

Projection Mapping ◽

Positron Emission ◽

Neuronal Projection ◽

Compound 21 ◽

First Time

AbstractDesigner 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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Deschloroclozapine, a potent and selective chemogenetic actuator enables rapid neuronal and behavioral modulations in mice and monkeys

10.1101/854513 ◽

2019 ◽

Cited By ~ 2

Author(s):

Yuji Nagai ◽

Naohisa Miyakawa ◽

Hiroyuki Takuwa ◽

Yukiko Hori ◽

Kei Oyama ◽

...

Keyword(s):

Neuronal Activity ◽

Spatial Working Memory ◽

Memory Deficits ◽

Designer Drugs ◽

Systemic Delivery ◽

Selective Agonist ◽

Positron Emission ◽

And Behavior ◽

Fast Acting ◽

Target Effects

AbstractThe chemogenetic technology Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) affords remotely reversible control of cellular signaling, neuronal activity and behavior. Although the combination of muscarinic-based DREADDs with clozapine-N-oxide (CNO) has been widely used, sluggish kinetics, metabolic liabilities, and potential off-target effects of CNO represent areas for improvement. Here we provide a new high affinity and selective agonist deschloroclozapine (DCZ) for muscarinic-based DREADDs. Positron emission tomography revealed that DCZ selectively bound to and occupied DREADDs in both mice and monkeys. Systemic delivery of low doses of DCZ (1 or 3 μg/kg) enhanced neuronal activity via hM3Dq within minutes in mice and monkeys. Intramuscular injections of DCZ (100 μg/kg) reversibly induced spatial working memory deficits in monkeys expressing hM4Di in the prefrontal cortex. DCZ represents the most potent, selective, metabolically stable and fast-acting DREADD agonist reported with utility in both mice and non-human primates for a variety of applications.

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