Glu-Ureido-Based Inhibitors of Prostate-Specific Membrane Antigen: Lessons Learned During the Development of a Novel Class of Low-Molecular-Weight Theranostic Radiotracers
Glu-Ureido-Based Inhibitors of Prostate-Specific Membrane Antigen: Lessons Learned During the Development of a Novel Class of Low-Molecular-Weight Theranostic Radiotracers
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DOI：
10.2967/jnumed.116.186775
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发表时间：
2017-09-01
影响因子：
9.3
通讯作者：
Babich, John
中科院分区：
文献类型：
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作者：
Kopka, Klaus;Benesova, Martina;Babich, John
近年来，几种靶向前列腺特异性膜抗原（PSMA）的放射性配体已被引入临床，作为一类新的治疗诊断放射性药物用于治疗前列腺癌（PC）。在世纪的第二个十年，在F-18-FDG临床引入40年后，小分子PSMA抑制剂放射性配体的临床引入开启了核医学的新时代。由于PC的高发病率和高死亡率，新型PSMA放射性配体已经对PC的临床治疗产生了显著影响。为了治疗诊断药物的持续临床开发和长期成功，设计治疗诊断核医学的现代前瞻性临床试验至关重要。使用源自小分子PSMA抑制剂的PSMA放射性配体进行的首次人体研究显示，通过PET和SPECT对PSMA阳性PC进行了高灵敏度成像，以及PSMA放射性配体治疗后转移性去势抵抗性PC的显著反应。这一巨大的成功在逻辑上导致了几种PSMA放射性配体的前瞻性临床试验的开始。与此同时，MIP-1404、PSMA-11、2-（3-{1-羧基-5-[（6-氟-吡啶-3-羰基）-氨基]-戊基}-脲基）戊二酸（DCFPyL）、PSMA-617、PSMA-1007等已经或即将在几个国家进入前瞻性临床试验。例如，从2013年到2016年，关于PSMA靶向PET成像的出版物数量大幅增加（例如，在Web of Science中搜索“PSMA”和“PET”，在2013年仅发现19篇出版物，但在2016年发现218篇）。对PSMA抑制剂放射性示踪剂治疗PC的初步成功进行更仔细的检查，从基础研究的角度以及从临床需求的角度提出了几个问题：关于已经开发的PSMA放射性配体的设计，我们学到了什么教训？在最佳PSMA放射性配体设计和广泛的临床需求之间是否达到了可接受的折衷？从PSMA经验中的多次成功中吸取的经验教训能否转移到进一步的治疗诊断方法中？
In recent years, several radioligands targeting prostate-specific membrane antigen (PSMA) have been clinically introduced as a new class of theranostic radiopharmaceuticals for the treatment of prostate cancer (PC). In the second decade of the 21st century, a new era in nuclear medicine was initiated by the clinical introduction of small-molecule PSMA inhibitor radioligands, 40 y after the clinical introduction of F-18-FDG. Because of the high incidence and mortality of PC, the new PSMA radioligands have already had a remarkable impact on the clinical management of PC. For the continuing clinical development and long-term success of theranostic agents, designing modern prospective clinical trials in theranostic nuclear medicine is essential. First-in-human studies with PSMA radioligands derived from small-molecule PSMA inhibitors showed highly sensitive imaging of PSMA-positive PC by means of PET and SPECT as well as a dramatic response of metastatic castration-resistant PC after PSMA radioligand therapy. This tremendous success logically led to the initiation of prospective clinical trials with several PSMA radioligands. Meanwhile, MIP-1404, PSMA-11, 2-(3-{1-carboxy-5-[(6-fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)pentanedioic acid (DCFPyL), PSMA-617, PSMA-1007, and others have entered or will enter prospective clinical trials soon in several countries. The significance becomes apparent by, for example, the considerable increase in the number of publications about PSMA-targeted PET imaging from 2013 to 2016 (e.g., a search of the Web of Science for "PSMA" AND "PET" found only 19 publications in 2013 but 218 in 2016). Closer examination of the initial success of PC treatment with PSMA inhibitor radiotracers leads to several questions from the basic research perspective as well as from the perspective of clinical demands: What lessons have been learned regarding the design of PSMA radioligands that have already been developed? Has an acceptable compromise between optimal PSMA radioligand design and a broad range of clinical demands been reached? Can the lessons learned from multiple successes within the PSMA experience be transferred to further theranostic approaches?