64Cu production via the 68Zn(p,nα)64Cu nuclear reaction: An untapped, cost-effective and high energy production route

IF 3.6 4区 医学 Q1 RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING
Bryce J.B. Nelson , Samantha Leier , John Wilson , Melinda Wuest , Jonathan Doupe , Jan D. Andersson , Frank Wuest
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引用次数: 0

Abstract

Introduction

Copper-64 (64Cu, t1/2 = 12.7 h) is a positron emitter well suited for theranostic applications with beta-emitting 67Cu for targeted molecular imaging and radionuclide therapy. The present work aims to evaluate the radionuclidic purity and radiochemistry of 64Cu produced via the 68Zn(p,nα)64Cu nuclear reaction. Macrocyclic chelators DOTA, NOTA, TETA, and prostate-specific membrane antigen ligand PSMA I&T were radiolabeled with purified 64Cu and tested for in vitro stability. [64Cu]Cu-PSMA I&T was used to demonstrate in vivo PET imaging using 64Cu synthesized via the 68Zn(p,nα)64Cu production route and its suitability as a theranostic imaging partner alongside 67Cu therapy.

Methods

64Cu was produced on a 24 MeV TR-24 cyclotron at a beam energy of 23.5 MeV and currents up to 70 μA using 200 mg 68Zn encapsulated within an aluminum‑indium-graphite sealed solid target assembly. 64Cu semi-automated purification was performed using a NEPTIS Mosaic-LC synthesis unit employing CU, TBP, and TK201 (TrisKem) resins. Radionuclidic purity was measured by HPGe gamma spectroscopy, while ICP-OES assessed elemental purity. Radiolabeling was performed with NOTA at room temperature and DOTA, TETA, and PSMA I&T at 95 °C. 64Cu incorporation was studied by radio-TLC. 64Cu in vitro stability of [64Cu]Cu-NOTA, [64Cu]Cu-DOTA, [64Cu]Cu-TETA, and [64Cu]Cu-PSMA I&T was assessed at 37 °C from 0 to 72 h in human blood serum. Preclinical PET imaging was performed at 1, 24, and 48 h post-injection with [64Cu]Cu-PSMA I&T in LNCaP tumor-bearing mice and compared with [68Ga]Ga-PSMA I&T.

Results

Maximum purified activity of 4.9 GBq [64Cu]CuCl2 was obtained in 5 mL of pH 2–3 solution, with 2.9 GBq 64Cu concentrated in 0.5 mL. HPGe gamma spectroscopy of purified 64Cu detected <0.3 % co-produced 67Cu at EOB with no other radionuclidic impurities. ICP-OES elemental analysis determined <1 ppm Al, Zn, In, Fe, and Cu in the [64Cu]CuCl2 product. NOTA, DOTA, TETA, and PSMA I&T were radiolabeled with 64Cu, resulting in maximum molar activities of 164 ± 6 GBq/μmol, 155 ± 31 GBq/μmol, 266 ± 34 GBq/μmol, and 117 ± 2 GBq/μmol, respectively. PET imaging in PSMA-expressing LNCaP xenografts resulted in high tumor uptake (SUVmean = 1.65 ± 0.1) using [64Cu]Cu-PSMA I&T, while [68Ga]Ga-PSMA I&T yielded an SUVmean of 0.76 ± 0.14 after 60 min post-injection.

Conclusions

64Cu was purified in a small volume amenable for radiolabeling, with yields suitable for preclinical and clinical application. The 64Cu production and purification process and the favourable PET imaging properties confirm the 68Zn(p,nα)64Cu nuclear reaction as a viable 64Cu production route for facilities with access to a higher energy proton cyclotron, compared to using expensive 64Ni target material and the 64Ni(p,n)64Cu nuclear reaction.

Advances in knowledge and implications for patient care

Our 64Cu production technique provides an alternative production route with the potential to improve 64Cu availability for preclinical and clinical studies alongside 67Cu therapy.

Abstract Image

Abstract Image

通过 68Zn(p,nα)64Cu 核反应生产 64Cu:一条尚未开发的、具有成本效益的高能生产路线
导言铜-64(64Cu,t1/2 = 12.7 h)是一种正电子发射体,非常适合与β发射的 67Cu 一起用于治疗学应用,以进行靶向分子成像和放射性核素治疗。本研究旨在评估通过 68Zn(p,nα)64Cu 核反应生成的 64Cu 的放射性核素纯度和放射化学性质。用纯化的 64Cu 对大环螯合剂 DOTA、NOTA、TETA 和前列腺特异性膜抗原配体 PSMA I&T 进行放射性标记,并测试其体外稳定性。使用 68Zn(p,nα)64Cu 生产路线合成的 64Cu 及其作为 67Cu 治疗的治疗成像伙伴的适用性,演示了 [64Cu]Cu-PSMA I&T 的体内 PET 成像。使用 NEPTIS Mosaic-LC 合成装置,采用 CU、TBP 和 TK201(TrisKem)树脂,对 64Cu 进行了半自动纯化。放射性核素纯度通过 HPGe 伽马光谱进行测量,而 ICP-OES 则对元素纯度进行评估。用 NOTA 在室温下进行放射性标记,用 DOTA、TETA 和 PSMA I&T 在 95 °C 下进行放射性标记。64Cu 的掺入通过放射性-TLC 进行了研究。评估了[64Cu]Cu-NOTA、[64Cu]Cu-DOTA、[64Cu]Cu-TETA 和 [64Cu]Cu-PSMA I&T 在 37 °C、0 至 72 小时内人血清中的 64Cu 体外稳定性。结果在 5 mL pH 2-3 溶液中获得最大纯化活性 4.9 GBq [64Cu]CuCl2,其中 2.9 GBq 64Cu 浓缩在 0.5 mL 中。对纯化的 64Cu 进行 HPGe 伽马光谱分析,在 EOB 检测到 0.3 % 的共生 67Cu,没有其他放射性核素杂质。ICP-OES元素分析测定出[64Cu]CuCl2产物中含有1 ppm的铝、锌、铟、铁和铜。用 64Cu 对 NOTA、DOTA、TETA 和 PSMA I&T 进行了放射性标记,其最大摩尔活度分别为 164 ± 6 GBq/μmol、155 ± 31 GBq/μmol、266 ± 34 GBq/μmol 和 117 ± 2 GBq/μmol。使用[64Cu]Cu-PSMA I&T对表达PSMA的LNCaP异种移植物进行正电子发射计算机断层成像后,肿瘤摄取率很高(SUVmean = 1.65 ± 0.1),而[68Ga]Ga-PSMA I&T在注射后60分钟的SUVmean为0.76 ± 0.14。与使用昂贵的 64Ni 靶材和 64Ni(p,n)64Cu 核反应相比,64Cu 的生产和提纯过程以及良好的 PET 成像特性证实了 68Zn(p,nα)64Cu 核反应是一种可行的 64Cu 生产途径,适合于有条件使用高能质子回旋加速器的设施。
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来源期刊
Nuclear medicine and biology
Nuclear medicine and biology 医学-核医学
CiteScore
6.00
自引率
9.70%
发文量
479
审稿时长
51 days
期刊介绍: Nuclear Medicine and Biology publishes original research addressing all aspects of radiopharmaceutical science: synthesis, in vitro and ex vivo studies, in vivo biodistribution by dissection or imaging, radiopharmacology, radiopharmacy, and translational clinical studies of new targeted radiotracers. The importance of the target to an unmet clinical need should be the first consideration. If the synthesis of a new radiopharmaceutical is submitted without in vitro or in vivo data, then the uniqueness of the chemistry must be emphasized. These multidisciplinary studies should validate the mechanism of localization whether the probe is based on binding to a receptor, enzyme, tumor antigen, or another well-defined target. The studies should be aimed at evaluating how the chemical and radiopharmaceutical properties affect pharmacokinetics, pharmacodynamics, or therapeutic efficacy. Ideally, the study would address the sensitivity of the probe to changes in disease or treatment, although studies validating mechanism alone are acceptable. Radiopharmacy practice, addressing the issues of preparation, automation, quality control, dispensing, and regulations applicable to qualification and administration of radiopharmaceuticals to humans, is an important aspect of the developmental process, but only if the study has a significant impact on the field. Contributions on the subject of therapeutic radiopharmaceuticals also are appropriate provided that the specificity of labeled compound localization and therapeutic effect have been addressed.
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