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

Abstract：

INTRODUCTION: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. 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 D4 radioligand candidates for in vivo imaging. RESULTS: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. CONCLUSIONS: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. ADVANCES IN KNOWLEDGE:The discovery of new lead structures for high-affinity D4 ligands opens up new possibilities for the development of suitable PET-radioligands. IMPLICATIONS FOR PATIENT:PET-imaging of dopamine D4-receptors could facilitate understanding, diagnosis and treatment of neuropsychiatric and neurodegenerative diseases.

journal_name

Nucl Med Biol

journal_title

Nuclear medicine and biology

authors

Willmann M,Ermert J,Prante O,Hübner H,Gmeiner P,Neumaier B

doi

10.1016/j.nucmedbio.2020.07.004

subject

Has Abstract

pub_date

2020-07-16 00:00:00

eissn

0969-8051

issn

1872-9614

pii

S0969-8051(20)30195-5

pub_type

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