Universität zu Köln

Willmann, Michael, Ermert, Johannes ORCID: 0000-0002-2561-7766, Prante, Olaf, Huebner, Harald, Gmeiner, Peter and Neumaier, Bernd (2021). Radiosynthesis and evaluation of F-18-labeled dopamine D-4-receptor ligands. Nucl. Med. Biol., 92. S. 43 - 53. NEW YORK: ELSEVIER SCIENCE INC. ISSN 1872-9614

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Abstract

Introduction: The dopamine D-4 receptor (D4R) has attracted considerable attention as potential target for the treatment of a broad range of central nervous system disorders. Although many efforts have been made to improve the performance of putative radioligand candidates, there is still a lack of D4R selective tracers suitable for in vivo PET imaging. Thus, the objective of this work was to develop a D-4-selective PET ligand for clinical applications. Methods: Four compounds based on previous and new lead structures were prepared and characterized with regard to their D4R subtype selectivity and predicted lipophilicity. From these, 3-((4-(2-fluorophenyl)piperazin-1-yl)methyl)-1H-pyrrolo[2,3-b]pyridine I and (S)-4-(3-fluoro-4-methoxybenzyl)-2-(phenoxymethyl)morpholine II were selected for labeling with fluorine-18 and subsequent evaluation by in vitro autoradiography to assess their suitability as D-4 radioligand candidates for in vivo imaging. Results: The radiosynthesis of [F-18]I and [F-18]II was successfully achieved by copper-mediated radiofluorination with radiochemical yields of 7% and 66%, respectively. The radioligand [F-18]II showed specific binding in areas where D-4 expression is expected, whereas [F-18]I did not show any uptake in distinct brain regions and exhibited an unacceptable degree of non-specific binding. Conclusions: The compounds studied exhibited high D4R subtype selectivity and logP values compatible with high brain uptake, but only ligand [F-18]II showed low non-specific binding and is therefore a good candidate for further evaluation. Advances in knowledge: The discovery of new lead structures for high-affinity D-4 ligands opens up new possibilities for the development of suitable PET-radioligands. Implications for patient: PET-imaging of dopamine D-4-receptors could facilitate understanding, diagnosis and treatment of neuropsychiatric and neurodegenerative diseases. (C) 2020 Elsevier Inc. All rights reserved.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Willmann, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Ermert, Johannes UNSPECIFIED orcid.org/0000-0002-2561-7766 UNSPECIFIED Prante, Olaf UNSPECIFIED UNSPECIFIED UNSPECIFIED Huebner, Harald UNSPECIFIED UNSPECIFIED UNSPECIFIED Gmeiner, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Neumaier, Bernd UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-584809
DOI:	10.1016/j.nucmedbio.2020.07.004
Journal or Publication Title:	Nucl. Med. Biol.
Volume:	92
Page Range:	S. 43 - 53
Date:	2021
Publisher:	ELSEVIER SCIENCE INC
Place of Publication:	NEW YORK
ISSN:	1872-9614
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language Radiology, Nuclear Medicine & Medical Imaging Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/58480