Ahmanson Translational Imaging Division, David Geffen School of Medicine, University of California, Los Angeles, CA 90095.
Department of Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095.
Theranostics. 2019 Feb 14;9(5):1336-1347. doi: 10.7150/thno.31806. eCollection 2019.
The trend to inform personalized molecular radiotherapy with molecular imaging diagnostics, a concept referred to as theranostics, has transformed the field of nuclear medicine in recent years. The development of theranostic pairs comprising somatostatin receptor (SSTR)-targeting nuclear imaging probes and therapeutic agents for the treatment of patients with neuroendocrine tumors (NETs) has been a driving force behind this development. With the Neuroendocrine Tumor Therapy (NETTER-1) phase 3 trial reporting encouraging results in the treatment of well-differentiated, metastatic midgut NETs, peptide radioligand therapy (RLT) with the Lu-labeled somatostatin analog (SSA) [Lu]Lu-DOTA-TATE is now anticipated to become the standard of care. On the diagnostics side, the field is currently dominated by Ga-labeled SSAs for the molecular imaging of NETs with positron emission tomography-computed tomography (PET/CT). PET/CT imaging with SSAs such as [Ga]Ga-DOTA-TATE, [Ga]Ga-DOTA-TOC, and [Ga]Ga-DOTA-NOC allows for NET staging with high accuracy and is used to qualify patients for RLT. Driven by the demand for PET/CT imaging of NETs, a commercial kit for the production of [Ga]Ga-DOTA-TATE (NETSPOT) was approved by the U.S. Food and Drug Administration (FDA). The synthesis of Ga-labeled SSAs from a Ge/Ga-generator is straightforward and allows for a decentralized production, but there are economic and logistic difficulties associated with these approaches that warrant the search for a viable, generator-independent alternative. The clinical introduction of an F-labeled SSTR-imaging probe can help mitigate the shortcomings of the generator-based synthesis approach, but despite extensive research efforts, none of the proposed F-labeled SSAs has been translated past prospective first-in-humans studies so far. Here, we review the current state of probe-development from a translational viewpoint and make a case for a clinically viable, F-labeled alternative to the current standard [Ga]Ga-DOTA-TATE.
近年来，将分子成像诊断应用于个性化分子放疗（被称为治疗诊断学）的趋势已经改变了核医学领域。包含生长抑素受体（SSTR）靶向核成像探针和用于治疗神经内分泌肿瘤（NET）患者的治疗剂的治疗诊断对的发展是这一趋势的主要推动力。随着神经内分泌肿瘤治疗（NETTER-1）的第 3 期临床试验在治疗分化良好的转移性中肠 NET 方面取得了令人鼓舞的结果，用 Lu 标记的生长抑素类似物（SSA）[Lu]Lu-DOTA-TATE 的肽放射性配体治疗（RLT）现在有望成为标准治疗。在诊断方面，目前 Ga 标记的 SSA 占据主导地位，用于 NET 的正电子发射断层扫描-计算机断层扫描（PET/CT）分子成像。SSA（如[Ga]Ga-DOTA-TATE、[Ga]Ga-DOTA-TOC 和[Ga]Ga-DOTA-NOC）的 PET/CT 成像可实现 NET 的高准确性分期，并用于为 RLT 筛选患者。由于对 NET 的 PET/CT 成像的需求，一种用于生产[Ga]Ga-DOTA-TATE（NETSPOT）的商业试剂盒获得了美国食品和药物管理局（FDA）的批准。从 Ge/Ga 发生器合成 Ga 标记的 SSA 很简单，可以实现分散式生产，但这些方法存在经济和物流方面的困难，需要寻找可行的、不依赖发生器的替代方法。F 标记的 SSTR 成像探针的临床引入可以帮助减轻基于发生器合成方法的缺点，但尽管进行了广泛的研究，迄今为止，没有一种提出的 F 标记的 SSA 能够超越前瞻性的首次人体研究。在这里，我们从转化的角度回顾了目前的探针开发状态，并提出了一种可行的、临床用的、替代目前标准的[Ga]Ga-DOTA-TATE 的 F 标记的替代方法。
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