Development of high-affinity fluorinated ligands for cannabinoid subtype 2 receptor, and in vitro evaluation of a radioactive tracer for imaging.

Autor: Modemann DJ; Clinic of Nuclear Medicine, University Medicine Göttingen (UMG), Germany., Mahardhika AB; Pharmaceutical Institute, Department of Pharmaceutical & Medicinal Chemistry, University of Bonn, Germany; Research Training Group GRK1873, University of Bonn, Germany., Yamoune S; Federal Institute for Drugs and Medical Devises, Research Division, BfArM Bonn, Germany; Institute of Clinical Pharmacology, University Hospital RWTH Aachen, Germany., Kreyenschmidt AK; Institute of Inorganic Chemistry, Georg-August-University Göttingen, Germany., Maaß F; Max-Planck-Institute for Experimental Medicine, Göttingen, Germany., Kremers S; Pharmaceutical Institute, Department of Pharmaceutical & Medicinal Chemistry, University of Bonn, Germany., Breunig C; Clinic of Nuclear Medicine, University Medicine Göttingen (UMG), Germany., Sahlmann CO; Clinic of Nuclear Medicine, University Medicine Göttingen (UMG), Germany., Bucerius J; Clinic of Nuclear Medicine, University Medicine Göttingen (UMG), Germany., Stalke D; Institute of Inorganic Chemistry, Georg-August-University Göttingen, Germany., Wiltfang J; Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany; German Center for Neurodegenerative Diseases (DZNE), Research Site Göttingen, Germany; Neurosciences and Signaling Group, Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, Aveiro, Portugal., Bouter Y; Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany., Müller CE; Pharmaceutical Institute, Department of Pharmaceutical & Medicinal Chemistry, University of Bonn, Germany; Research Training Group GRK1873, University of Bonn, Germany., Bouter C; Clinic of Nuclear Medicine, University Medicine Göttingen (UMG), Germany., Meller B; Clinic of Nuclear Medicine, University Medicine Göttingen (UMG), Germany. Electronic address: birgit.meller@med.uni-goettingen.de.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2022 Mar 15; Vol. 232, pp. 114138. Date of Electronic Publication: 2022 Jan 28.
DOI: 10.1016/j.ejmech.2022.114138
Abstrakt: The development of neurodegenerative diseases is associated with cerebral inflammation, which activates resident immune cells of the central nervous system (CNS), namely microglial cells that show an up-regulation of the cannabinoid subtype 2 receptor (CB 2 R) expression. Therefore our work aimed to design and synthesize a radiotracer for the detection of CB 2 R expression by positron emission tomography (PET) allowing an early diagnosis of neurodegenerative diseases. For the development of such a PET tracer, N-alkyl-substituted indole-3-yl-tetramethylcyclopropylketones served as lead structures due to their high CB 2 R potency and selectivity, allowing radiolabeling on the N-alkyl chain. To this end, eight novel fluorinated N-alkyl-indole-3-yl-tetramethylcyclopropylketones were synthesized, investigated in radioligand binding studies, and structure-activity relationships were evaluated. The most promising candidate was (1-(4-fluoropropyl)-1H-indole-3-yl)(2,2,3,3-tetramethyl-cyclopropyl)methanone (K i : 7.88 nM at the CB 2 R, 3430 nM at cannabinoid subtype 1 receptor (CB 1 R)). A precursor was synthesized, radiofluorinated with no-carrier-added [ 18 F]F - by nucleophilic substitution of a tosyl group, and the resulting PET ligand was purified, all being performed on a fully automated synthesis module. The tracer was produced in 34 ± 6% radiochemical yield within 2 h and with molar activities of up to 1500 GBq/μmol. A first preclinical evaluation was carried out including determination of logP, metabolic stability by liver microsomes, and autoradiography. The novel PET tracer for imaging CB 2 R showed promising results warranting subsequent clinical evaluation.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2022. Published by Elsevier Masson SAS.)
Databáze: MEDLINE
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