A new technique to make 68Ga-labeled pharmaceuticals widely available for clinical use

摘要 前列腺癌是男性最常见的恶性肿瘤。在大约三分之一的新诊断的 前列腺癌，这种疾病是无痛的，不需要特殊的治疗。在三分之一的患者中， 这种疾病可以通过手术或放射治疗治愈，但其余三分之一的患者在初次治疗后复发。 治疗，需要额外的治疗。前列腺癌的治疗方法有哪些？ 用于表征前列腺癌的侵袭性，检测转移性疾病， 以及监测肿瘤对治疗的反应。然而，一种新的PET显像剂68 Ga-PSMA-DKFZ-11 （68 Ga-PSMA），最近在迄今为止的临床研究中显示出巨大的前景，特别是由于其特殊的 复发性和转移性前列腺癌定位的准确性。 镓-68（68 Ga）是分子成像的理想放射性同位素，因为其半衰期短且共轭 潜在的生物分子。然而，其更广泛的临床应用的一个主要障碍 在前列腺癌等疾病中的实施缺乏广泛可用且具有成本效益的来源 68 Ga的。NCM USA，LLC开发了一种在医用回旋加速器中产生数Ci 68 Ga的新技术 使用（68 Zn，p，n）工艺。相比之下，使用68 Ge/68 Ge发生器的当前技术可以产生50 mCi最多为68 Ga。MSK和NCM合作的目的是确定68 Ga-PSMA是否可以 以具有成本效益的方式用回旋加速器产生的68 Ga进行放射性标记，并在几个小时内运送到临床 位点，类似于18F-氟脱氧葡萄糖的当前分布模型。必须解决的挑战 为了使回旋加速器生产的68 Ga商业化，需要优化68 Zn目标的质量 生产和运输过程中比活性损失对肿瘤摄取68 Ga-PSMA的潜在影响。 因此，我们提出了一个三管齐下的办法，我们将（i）确定具体活动对 68 Ga-PSMA的肿瘤摄取，（ii）设计和构建优化的68 Zn靶和自动68 Ga标记 系统，和（iii）进行临床试验，比较回旋加速器产生的68 Ga-PSMA与发生器产生的 68Ga。如果成功，该提案不仅为68 Ga-PSMA的临床使用铺平了道路，而且还为其他 68 Ga标记的放射性药物，如受体配体，以及肺和心肌灌注剂。

ABSTRACT Prostate cancer is the most common malignancy in men. In approximately one third of newly diagnosed prostate cancers, the disease is indolent and does not require specific treatment. In one third of the patients the disease can be cured by surgery or radiotherapy, but the remaining third of patients recurs after initial therapy and require additional treatment. Adequate treatment of prostate cancer is hampered by a lack of imaging techniques for characterizing the aggressiveness of prostate cancer, detecting metastatic disease, and monitoring tumor response to therapy. However, one new PET imaging agent, 68Ga-PSMA-DKFZ-11 (68Ga-PSMA), has recently shown enormous promise in clinical studies to date, particularly for its exceptional accuracy in localizing recurrent and metastatic prostate cancer. Gallium-68 (68Ga) is an ideal radioisotope for molecular imaging, given its short half-life and conjugation potential with a wide array of biological molecules. However, one major obstacle for its broader clinical implementation in diseases such as prostate cancer is the lack of a widely available and cost-effective source of 68Ga. NCM USA, LLC has developed a new technique to produce several Ci of 68Ga in a medical cyclotron using a (68Zn,p,n) process. In contrast, the current technique using the 68Ge/68Ge generator can produce 50 mCi of 68Ga at most. The purpose of the collaboration of MSK and NCM is to establish if 68Ga-PSMA can be radiolabeled with cyclotron-produced 68Ga in a cost-efficient way and shipped over several hours to clinical sites, similar to the current distribution model of 18F-fluorodeoxyglucose. Challenges that must be addressed for the commercialization of cyclotron-produced 68Ga are the optimization of the 68Zn target for mass production and the potential impact of loss of specific activity during transport on tumor uptake of 68Ga-PSMA. We therefore propose a three-pronged approach in which we will (i) determine the impact of specific activity on tumor uptake of 68Ga-PSMA, (ii) design and build an optimized 68Zn target and automated 68Ga-labeling system, and (iii) conduct a clinical trial comparing cyclotron-produced 68Ga-PSMA with generator-produced 68Ga. If successful, this proposal will not only pave the way for clinical use of 68Ga-PSMA, but also for other 68Ga-labeled radiopharmaceuticals, such as receptor ligands, as well as lung and myocardial perfusion agents.