Radiosynthesis and evaluation of 18F-labeled dopamine D4-receptor ligands

• Published in: Nuclear medicine and biology 2021-01, Vol.92, p.43-52
• Main Authors: Willmann, Michael, Ermert, Johannes, Prante, Olaf, Hübner, Harald, Gmeiner, Peter, Neumaier, Bernd
• Format: Article
• Language: English
• Subjects: 18F-Labeling; Autoradiography; Binding; Brain; Central nervous system; Dopamine; Dopamine D4 receptors; Dopamine D4-receptor; Fluorine; Fluorine isotopes; Health services; Lead; Ligands; Medical imaging; Medical treatment; Mental disorders; Morpholine; Neurodegenerative diseases; Neuroimaging; Neurological diseases; Positron emission; Positron emission tomography; Pyridines; Radiochemistry; Radioisotopes; Receptors; Schizophrenia; Selectivity; Tomography; Tracers
• ISSN: 0969-8051; 1872-9614; 1872-9614
• DOI: 10.1016/j.nucmedbio.2020.07.004

The dopamine D4 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 D4-selective PET ligand for clinical applications. 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 D4 radioligand candidates for in vivo imaging. The radiosynthesis of [18F]I and [18F]II was successfully achieved by copper-mediated radiofluorination with radiochemical yields of 7% and 66%, respectively. The radioligand [18F]II showed specific binding in areas where D4 expression is expected, whereas [18F]I did not show any uptake in distinct brain regions and exhibited an unacceptable degree of non-specific binding. The compounds studied exhibited high D4R subtype selectivity and logP values compatible with high brain uptake, but only ligand [18F]II showed low non-specific binding and is therefore a good candidate for further evaluation. The discovery of new lead structures for high-affinity D4 ligands opens up new possibilities for the development of suitable PET-radioligands. PET-imaging of dopamine D4-receptors could facilitate understanding, diagnosis and treatment of neuropsychiatric and neurodegenerative diseases.