背景:锆-89(89Zr)是一种正电子发射体,与其他较短寿命的正电子发射断层扫描(PET)兼容的放射性金属(例如镓-68或铜-64)相比具有几个优点。这些包括几乎无限的可用性,极低的成本,大大促进了配送物流,正电子能量适合医学PET成像,和足够长的物理半衰期,以便在稍后的时间点进行PET成像,以进行患者特异性剂量测定评估。尽管有这些明显的好处,89Zr在核医学界的接收一直不温不火。缺乏更广泛适应的驱动因素主要在其最终制剂-[89Zr]草酸锆中进行。当作为金标准螯合剂去铁胺(DFO)的合适前体溶液时,[89Zr]Zr-草酸盐是最常用的螯合剂,如大环DOTA,由于其预螯合状态。因此,多个研究小组进行了开创性工作,以创建无草酸盐形式的[89Zr]Zr4+,通过将草酸盐化学转化为其他抗衡离子形式或通过直接放射化学分离[89Zr]ZrCl4,表明[89Zr]Zr-DOTA络合物是可能且稳定的。然而,这种成功伴随着挑战,包括复杂和劳动密集型的放射化学处理和放射性标记程序,以及相对微小的转化率。这里,我们报告了[89Zr]ZrCl4的直接生产,避免了草酸盐和金属污染物,以实现DOTA构建体的有效放射性标记。
方法:我们基于先前报道的方法直接生产[89Zr]ZrCl4,并通过使用TK400树脂进行额外的除铁步骤进一步优化了质量。这里,我们避免使用草酸,并有效地减少了痕量金属污染物的含量。我们的两步纯化程序是自动化的,我们证实了优良的放射性核素纯度,微量金属含量,随着时间的推移,反应能力很强,高比摩尔活性。此外,对基于DOTA的PSMA-617和基于DOTAGA的PSMA-I&T进行放射性标记,以证明直接放射性标记的可行性并估计最大表观比活性。最后,在携带PC3-PIP异种移植物的小鼠中评估[89Zr]Zr-PSMA-617的生物分布,并将结果与先前发表的数据进行比较。
结果:共18批,范围从6.9到20GBq(186到541mCi),是生产出来的。[89Zr]ZrCl4的比摩尔活性超过0.96GBq(26mCi)/纳摩尔锆。放射性核素纯度>99%,并且痕量金属含量在<1ppm的范围内。当储存在环烯烃聚合物(COP)小瓶中时,[89Zr]ZrCl4保持其反应性化学形式至少五天。[89Zr]Zr-PSMA-617的11.1GBq(300mCi)和[89Zr]Zr-PSMA-I&T的14.4GBq(390mCi)批次,对应于11.1MBq/μg(0.3mCi/μg)的比活度,和14.4MBq/μg(0.39mCi/μg),分别,是生产出来的。[89Zr]Zr-PSMA-617动物PET成像结果与先前发表的数据一致。
结论:在这项工作中,我们报告了TK400树脂在[89Zr]ZrCl4放射化学分离过程中去除铁的合适应用。该突破允许用[89Zr]ZrCl4直接放射性标记基于DOTA的构建体,导致高表观摩尔活性和优异的转化率。
BACKGROUND: Zirconium-89 (89Zr) is a positron emitter with several advantages over other shorter-lived positron emission tomography (PET) compatible radiometals such as gallium-68 or copper-64. These include practically unlimited availability, extremely low cost, greatly facilitated distribution logistics, positron energy fit for medical PET imaging, and sufficiently long physical half-life to enable PET imaging at later time points for patient-specific dosimetry estimations. Despite these apparent benefits, the reception of 89Zr in the nuclear medicine community has been tepid. The driving factor for the absence of broader adaptation is mostly routed in its final formulation - [89Zr]zirconium oxalate. While serving as a suitable precursor solution for the gold standard chelator deferoxamine (DFO), [89Zr]Zr-oxalate is inaccessible for the most commonly used chelators, such as the macrocyclic
DOTA, due to its pre-chelated state. Consequently, pioneering work has been conducted by multiple research groups to create oxalate-free forms of [89Zr]Zr4+, either via chemical conversion of oxalate into other counterion forms or via direct radiochemical isolation of [89Zr]ZrCl4, showing that [89Zr]Zr-
DOTA complexes are possible and stable. However, this success was accompanied by challenges, including complex and labor-intensive radiochemical processing and radiolabeling procedures as well as the relatively minuscule conversion rates. Here, we report on the direct production of [89Zr]ZrCl4 avoiding oxalate and metal contaminants to enable efficient radiolabeling of
DOTA constructs.
METHODS: We based our direct production of [89Zr]ZrCl4 on previously reported methods and further optimized its quality by including an additional iron-removing step using the TK400 Resin. Here, we avoided using oxalic acid and effectively minimized the content of trace metal contaminants. Our two-step purification procedure was automated, and we confirmed excellent radionuclide purity, minimal trace metals content, great reactivity over time, and high specific molar activity. In addition,
DOTA-based PSMA-617 and DOTAGA-based PSMA-I&T were radiolabeled to demonstrate the feasibility of direct radiolabeling and to estimate the maximum apparent specific activities. Lastly, the biodistribution of [89Zr]Zr-PSMA-617 was assessed in mice bearing PC3-PIP xenografts, and the results were compared to the previously published data.
RESULTS: A total of 18 batches, ranging from 6.9 to 20 GBq (186 to 541 mCi), were produced. The specific molar activity for [89Zr]ZrCl4 exceeded 0.96 GBq (26 mCi) per nanomole of zirconium. The radionuclidic purity was >99 %, and the trace metals content was in the <1 ppm range. The [89Zr]ZrCl4 remained in its reactive chemical form for at least five days when stored in cyclic olefin polymer (COP) vials. Batches of 11.1 GBq (300 mCi) of [89Zr]Zr-PSMA-617 and 14.4 GBq (390 mCi) of [89Zr]Zr-PSMA-I&T, corresponding to specific activities of 11.1 MBq/μg (0.3 mCi/μg), and 14.4 MBq/μg (0.39 mCi/μg), respectively, were produced. [89Zr]Zr-PSMA-617 animal PET imaging results were in agreement with the previously published data.
CONCLUSIONS: In this work, we report on a suitable application of TK400 Resin to remove iron during [89Zr]ZrCl4 radiochemical isolation. The breakthrough allows for direct radiolabeling of
DOTA-based constructs with [89Zr]ZrCl4, leading to high apparent molar activities and excellent conversion rates.