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

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.