Radiosynthesis and evaluation of F-18-labeled dopamine D-4-receptor ligands

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