Positron-labeled DOPA analogs to image dopamine terminals
Positron-labeled DOPA analogs to image dopamine terminals
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DOI：
10.1002/ddr.10223
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发表时间：
2003-06-01
影响因子：
3.8
通讯作者：
DeJesus, OT
中科院分区：
文献类型：
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作者：
DeJesus, OT
多巴胺功能改变与帕金森氏病(PD)和其他运动障碍、精神分裂症、药物滥用、注意力缺陷障碍和其他神经精神疾病等疾病有关。开发用于多巴胺终端的PET显像剂的一个有用的方法是针对参与多巴胺生物合成的酶。酪氨酸羟化酶(TH)能将膳食中的L-对酪氨酸转化为L-3，4-二羟基苯丙氨酸(L-多巴)，这是多巴胺合成的第一步也是限速步骤。因此，TH靶向显像剂将是多巴胺神经元活动的理想PET示踪剂。然而，开发基于TH的示踪剂的努力到目前为止还没有成功。多巴胺合成的下一个酶是芳香族L-氨基酸脱羧酶，它将L-多巴转化为多巴胺。AAAD是开发多巴胺神经元显像剂的第一个靶点。第一个有用的AAAD PET示踪剂是6-[F-18]氟-L多巴(FDOPA)。后来，开发了一种实用的L-[β-C-11]多巴的合成方法。然而，由于标记的代谢物对PET图像的贡献，这些示踪剂对L-多巴的所有分解代谢途径的粘附性一直是一个缺点。因此，代谢更简单的替代示踪剂如氟L间酪氨酸(FMT)已被开发出来。对非人类灵长类动物的PET研究表明，FMT是含AAAD神经元的PET显像剂的选择。初步的人体研究表明，这种标记物在评估与AAAD相关的神经精神障碍方面是有用的。本文讨论了多巴胺PET示踪剂的起源和验证，并以对多巴胺系统的研究为例，描述了治疗药物开发和放射性药物开发之间的异同。(C)2003年Wiley-Liss，Inc.
Altered dopamine function has been implicated in disorders such as Parkinson's disease (PD) and other motor disorders, schizophrenia, substance abuse, attention deficit disorder, and other neuropsychiatric diseases. A useful approach to the development of PET imaging agents for dopamine terminals is to target the enzymes involved in dopamine biosynthesis. Tyrosine hydroxylase (TH) converts dietary L-p-tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA), which is the first and rate-limiting step in dopamine synthesis. Thus, a TH-targeted imaging agent would be the ideal PET tracer of dopamine neuronal activity. However, efforts to develop TH-based tracers have so far been unsuccessful. The next enzyme in dopamine synthesis is aromatic L-amino acid decarboxylase (AAAD), which converts L-DOPA to dopamine. AAAD was the first target in the development of imaging agents for dopamine neurons. The first useful AAAD PET tracer was 6-[F-18]Fluoro-L-DOPA (FDOPA). Later, a practicable synthesis of L-[beta-C-11]DOPA was developed. However, the adherence of these tracers to all the catabolic pathways of L-DOPA has been a disadvantage because of the contributions of labeled metabolites to PET images. Thus, alternative tracers with simpler metabolism such as fluoro-L-m-tyrosine (FMT) have been developed. PET studies in nonhuman primates have suggested that FMT is the PET imaging agent of choice for AAAD-containing neurons. Initial human studies show that this marker is useful in the assessment of AAAD-related neuropsychiatric disorders. This article discusses the origins and validation of dopamine PET tracers and delineates the similarities and differences between therapeutic drug development and radiopharmaceutical development as exemplified by studies on the dopamine system. (C) 2003 Wiley-Liss, Inc.