2. Academic Validation
  3. 18F-labeled radiotracers for in vivo imaging of DREADD with positron emission tomography

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.
Feng Hu 1,  Patrick J Morris 2,  Jordi Bonaventura 3,  Hong Fan 1,  William B Mathews 1,  Daniel P Holt 1,  Sherry Lam 3,  Matthew Boehm 3,  Robert F Dannals 1,  Martin G Pomper 1,  Michael Michaelides 4,  Andrew G Horti 5
Affiliations

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: [email protected].
PMID: 33280897 DOI: 10.1016/j.ejmech.2020.113047
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.

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