多巴胺D4受体(D4R)作为治疗广泛的中枢神经系统疾病的潜在靶标引起了广泛的关注。尽管已经做出了许多努力来改善假定的放射性配体候选物的性能,目前仍缺乏适用于体内PET成像的D4R选择性示踪剂。因此,这项工作的目的是开发用于临床应用的D4选择性PET配体.
制备了基于先前和新的前导结构的四种化合物,并对其D4R亚型选择性和预测的亲脂性进行了表征。从这些,选择3-((4-(2-氟苯基)哌嗪-1-基)甲基)-1H-吡咯并[2,3-b]吡啶I和(S)-4-(3-氟-4-甲氧基苄基)-2-(苯氧基甲基)吗啉II用氟-18标记,随后通过体外放射自显影进行评估,以评估其作为D4放射性配体候选物用于体内成像的适用性。
通过铜介导的放射性氟化成功地实现了[18F]I和[18F]II的放射合成,放射化学产率分别为7%和66%,分别。放射性配体[18F]II在预期D4表达的区域显示出特异性结合,而[18F]I在不同的大脑区域没有显示任何摄取,并且表现出不可接受的非特异性结合程度。
所研究的化合物表现出高D4R亚型选择性和与高大脑摄取相容的logP值,但只有配体[18F]II显示出低的非特异性结合,因此是进一步评估的良好候选者。
高亲和力D4配体的新先导结构的发现为开发合适的PET放射性配体开辟了新的可能性。
多巴胺D4受体的PET成像可以促进理解,神经精神和神经退行性疾病的诊断和治疗。
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.