F-labeled radiotracers for in vivo imaging of DREADD with positron emission tomography.

Designer Receptors Exclusively Activated by Designer Drugs (DREADD) are a preclinical chemogenetic approach with clinical potential for various disorders. In vivo visualization of DREADDs has been achieved with positron emission tomography (PET) using C radiotracers. The objective of this study was to develop DREADD radiotracers labeled with F for a longer isotope half-life. A series of non-radioactive fluorinated analogs of clozapine with a wide range of in vitro binding affinities for the hM3Dq and hM4Di DREADD receptors has been synthesized for PET. Compound [F]7b was radiolabeled via a modified F-deoxyfluorination protocol with a commercial ruthenium reagent. [F]7b demonstrated encouraging PET imaging properties in a DREADD hM3Dq transgenic mouse model, whereas the radiotracer uptake in the wild type mouse brain was low. [F]7b is a promising long-lived alternative to the DREADD radiotracers [C]clozapine ([C]CLZ) and [C]deschloroclozapine ([C]DCZ).