Fani Melpomeni, Nicolas Guillaume P, Wild Damian
Division of Nuclear Medicine, University Hospital Basel, Basel, Switzerland.
Division of Radiopharmaceutical Chemistry, University Hospital Basel, Basel, Switzerland; and.
J Nucl Med. 2017 Sep;58(Suppl 2):61S-66S. doi: 10.2967/jnumed.116.186783.
Somatostatin receptor (sstr) scintigraphy for imaging and sstr analogs for treatment have been used for more than 20 y. An important improvement in recent years was the introduction of peptide receptor radionuclide therapy with radiolabeled sstr agonists, such as [Y-DOTA,Tyr]octreotide or [Lu-DOTA,Tyr]octreotide (Y- or Lu-DOTATOC, respectively) and [Lu-DOTA,Tyr]octreotate (Lu-DOTATATE). PET/CT with Ga-labeled sstr agonists, such as Ga-DOTATOC, Ga-DOTATATE, and [Ga-DOTA,1-Nal]octreotide (Ga-DOTANOC), plays an important role in staging and restaging neuroendocrine tumors. Most importantly, sstr scintigraphy and sstr PET/CT can distinguish patients who will qualify for and benefit from peptide receptor radionuclide therapy. This characteristic of sstr targeting is important because it allows a personalized treatment approach (theranostic approach). Until recently, it was thought that internalization of the radiolabeled agonist was mandatory for sstr-mediated imaging and therapy. It was Ginj et al. who proposed in 2006 the paradigm shift that radiolabeled sstr antagonists may perform better than agonists despite the lack of internalization. Despite the rather limited number of head-to-head comparisons of sstr antagonists and agonists, the superiority of sstr antagonists was demonstrated in several cases. From a small library of sstr antagonists, the analog JR11 (Cpa-c[d-Cys-Aph(Hor)-d-Aph(Cbm)-Lys-Thr-Cys]-d-Tyr-NH), an antagonist with selectivity for sstr subtype 2, showed the best overall characteristics for sstr subtype 2 targeting and was therefore selected for clinical translation. JR11 is under clinical development as a PET imaging agent when labeled with Ga (Ga-NODAGA-JR11 or Ga-OPS202) and as a therapeutic agent when labeled with Lu (Lu-DOTA-JR11 or Lu-OPS201). In this article, we discuss the development and current status of radiolabeled sstr antagonists. Evidence based on preclinical work, on quantitative in vivo autoradiography of human tumor slices, and on human data now supports a shift to sstr antagonists.
生长抑素受体（sstr）闪烁扫描成像及生长抑素受体类似物治疗已应用超过20年。近年来的一项重要进展是引入了用放射性标记的生长抑素受体激动剂进行肽受体放射性核素治疗，如[Y - DOTA，Tyr]奥曲肽或[Lu - DOTA，Tyr]奥曲肽（分别为Y - 或Lu - DOTATOC）以及[Lu - DOTA，Tyr]奥曲肽（Lu - DOTATATE）。使用镓标记的生长抑素受体激动剂进行PET/CT检查，如Ga - DOTATOC、Ga - DOTATATE和[Ga - DOTA，1 - Nal]奥曲肽（Ga - DOTANOC），在神经内分泌肿瘤的分期及再分期中发挥着重要作用。最重要的是，生长抑素受体闪烁扫描成像及生长抑素受体PET/CT能够区分哪些患者适合并能从肽受体放射性核素治疗中获益。生长抑素受体靶向的这一特性很重要，因为它允许采用个性化治疗方法（诊疗一体化方法）。直到最近，人们一直认为放射性标记激动剂的内化对于生长抑素受体介导的成像和治疗是必不可少的。正是金吉等人在2006年提出了范式转变，即尽管缺乏内化作用，但放射性标记的生长抑素受体拮抗剂可能比激动剂表现更好。尽管生长抑素受体拮抗剂和激动剂的直接比较数量相当有限，但在一些病例中已证明生长抑素受体拮抗剂具有优越性。从一小批生长抑素受体拮抗剂库中，类似物JR11（Cpa - c[d - Cys - Aph(Hor) - d - Aph(Cbm) - Lys - Thr - Cys] - d - Tyr - NH），一种对生长抑素受体2亚型具有选择性的拮抗剂，在靶向生长抑素受体2亚型方面显示出最佳的总体特性，因此被选用于临床转化。当用镓标记时（Ga - NODAGA - JR11或Ga - OPS202），JR11作为PET成像剂正在进行临床开发；当用镥标记时（Lu - DOTA - JR11或Lu - OPS201），作为治疗剂进行临床开发。在本文中，我们讨论放射性标记的生长抑素受体拮抗剂的研发及现状。基于临床前研究、人体肿瘤切片定量体内放射自显影以及人体数据的证据现在支持向生长抑素受体拮抗剂的转变。
