18F-labeled radiotracers for in vivo imaging of DREADD with positron emission tomography

Feng Hu; Patrick J Morris; Jordi Bonaventura; Hong Fan; William B Mathews; Daniel P Holt; Sherry Lam; Matthew Boehm; Robert F Dannals; Martin G Pomper; Michael Michaelides; Andrew G Horti

doi:10.1016/j.ejmech.2020.113047

¹⁸F-labeled radiotracers for in vivo imaging of DREADD with positron emission tomography

Eur J Med Chem. 2021 Mar 5:213:113047. doi: 10.1016/j.ejmech.2020.113047. Epub 2020 Nov 25.

Authors

Affiliations

¹ Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA.
² Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, 20850, USA.
³ Biobehavioral Imaging and Molecular Neuropsychopharmacology Unit, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD, 21224, USA.
⁴ Biobehavioral Imaging and Molecular Neuropsychopharmacology Unit, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD, 21224, USA; Department of Psychiatry and behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, 221205, USA.
⁵ Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA. Electronic address: ahorti1@jhmi.edu.

Abstract

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 ¹¹C radiotracers. The objective of this study was to develop DREADD radiotracers labeled with ¹⁸F 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 [¹⁸F]7b was radiolabeled via a modified ¹⁸F-deoxyfluorination protocol with a commercial ruthenium reagent. [¹⁸F]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. [¹⁸F]7b is a promising long-lived alternative to the DREADD radiotracers [¹¹C]clozapine ([¹¹C]CLZ) and [¹¹C]deschloroclozapine ([¹¹C]DCZ).

Keywords: (18)F; Chemogenetics; DREADD; PET; SAR; hM3Dq; hM4Di.

MeSH terms

Animals
Brain / diagnostic imaging
Clozapine / chemistry*
Contrast Media / chemistry*
Diagnostic Techniques, Radioisotope
Fluorine Radioisotopes / chemistry*
Halogenation
Humans
Mice, Transgenic
Models, Animal
Positron-Emission Tomography / methods*
Radiopharmaceuticals / chemistry
Structure-Activity Relationship

Substances

Contrast Media
Fluorine Radioisotopes
Radiopharmaceuticals
Fluorine-18
Clozapine

Abstract

MeSH terms

Substances

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