Kopka Klaus, Benešová Martina, Bařinka Cyril, Haberkorn Uwe, Babich John
Division of Radiopharmaceutical Chemistry, German Cancer Research Center, INF 280, Heidelberg, Germany
German Cancer Consortium (DKTK), Heidelberg, Germany.
J Nucl Med. 2017 Sep;58(Suppl 2):17S-26S. doi: 10.2967/jnumed.116.186775.
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 21 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-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?
近年来，几种靶向前列腺特异性膜抗原（PSMA）的放射性配体已作为一类新型治疗诊断放射性药物被临床应用于前列腺癌（PC）的治疗。在21世纪的第二个十年，小分子PSMA抑制剂放射性配体的临床应用开启了核医学的新纪元，这距离F-FDG的临床应用已有40年。由于PC的高发病率和高死亡率，新型PSMA放射性配体已对PC的临床管理产生了显著影响。为了治疗诊断药物的持续临床开发和长期成功，设计现代前瞻性治疗诊断核医学临床试验至关重要。对源自小分子PSMA抑制剂的PSMA放射性配体进行的首次人体研究表明，通过PET和SPECT对PSMA阳性PC进行了高灵敏度成像，并且PSMA放射性配体治疗后转移性去势抵抗性PC有显著反应。这一巨大成功顺理成章地促使开展了多项PSMA放射性配体的前瞻性临床试验。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等已在多个国家进入或即将进入前瞻性临床试验。例如，2013年至2016年期间关于PSMA靶向PET成像的出版物数量大幅增加，这凸显了其重要性（例如，在科学网中搜索“PSMA”和“PET”，发现2013年仅有19篇出版物，而2016年有218篇）。从基础研究角度以及临床需求角度仔细审视PSMA抑制剂放射性示踪剂在PC治疗方面的初步成功会引发几个问题：关于已开发的PSMA放射性配体的设计，我们学到了哪些经验教训？在最佳PSMA放射性配体设计与广泛的临床需求之间是否达成了可接受的折衷方案？从PSMA研究中的多次成功所汲取的经验教训能否应用于进一步的治疗诊断方法？
