Copper-61 is an advantageous alternative to gallium-68 for PET imaging of somatostatin receptor-expressing tumors: a head-to-head comparative preclinical study.

Tais Basaco Bernabeu, Rosalba Mansi, Luigi Del Pozzo, Raghuvir Haridas Gaonkar, Lisa McDougall, Anass Johayem, Milen Blagoev, Francesco De Rose, Leila Jaafar-Thiel, Melpomeni Fani
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引用次数: 0

Abstract

Background: Gallium-68 positron emission tomography (68Ga-PET) with the two registered somatostatin analogs, [68Ga]Ga-DOTA-Tyr3-octreotide ([68Ga]Ga-DOTA-TOC) and [68Ga]Ga-DOTA-Tyr3-octreotate ([68Ga]Ga-DOTA-TATE), where DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, is routinely used for imaging of somatostatin receptor (SST)-expressing tumors. We investigated copper-61 (61Cu) as an alternative radiometal for PET imaging of SST-expressing tumors. Compared to gallium-68, copper-61 (t1/2 = 3.33 h, E β + max = 1.22 MeV) can be produced on a large scale, enables late time point imaging, and has the therapeutic twin copper-67. Herein, DOTA-TOC and 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid (NODAGA)-TOC were labeled with copper-61 and compared with the clinically used [68Ga]Ga-DOTA-TOC.

Methods: [61Cu]CuCl2 was produced from an irradiated natural nickel target. DOTA-TOC and NODAGA-TOC were labeled with [61Cu]CuCl2 in ammonium acetate buffer so to achieve a reaction pH of 5-6 and a temperature of 95°C for DOTA-TOC or room temperature for NODAGA-TOC. The radioligands were evaluated head-to-head in vitro using human embryonic kidney (HEK)-SST2 cells (affinity, binding sites, cellular uptake, and efflux) and in vivo using HEK-SST2 xenografts [PET/computed tomography (CT) imaging, biodistribution, and pharmacokinetics] and compared with [68Ga]Ga-DOTA-TOC, which was prepared using a standard procedure. Dosimetry estimates were made for [61Cu]Cu-NODAGA-TOC.

Results: [61Cu]Cu-DOTA-TOC and [61Cu]Cu-NODAGA-TOC were prepared at an apparent molar activity of 25 MBq/nmol with radiochemical purities of ≥96% and ≥98%, respectively. In vitro, both presented a sub-nanomolar affinity for SST2 (IC50 = 0.23 and 0.34 nM, respectively). They were almost entirely internalized upon binding to SST2-expressing cells and had similar efflux rates at 37°C. In vivo, [61Cu]Cu-DOTA-TOC and [61Cu]Cu-NODAGA-TOC showed the same accumulation in SST2-expressing tumors. However, PET/CT images and biodistribution analyses clearly showed an unfavorable biodistribution for [61Cu]Cu-DOTA-TOC, characterized by accumulation in the liver and the abdomen. [61Cu]Cu-NODAGA-TOC displayed favorable biodistribution, comparable with [68Ga]Ga-DOTA-TOC at 1 h post-injection (p.i.). Notwithstanding, [61Cu]Cu-NODAGA-TOC showed advantages at 4 h p.i., due to the tumor retention and improved tumor-to-non-tumor ratios. The effective dose (2.41 × 10-3 mSv/MBq) of [61Cu]Cu-NODAGA-TOC, but also the dose to the other organs and the kidneys (9.65 × 10-2 mGy/MBq), suggested a favorable safety profile.

Conclusion: Somatostatin receptor 61Cu-PET imaging not only matches the performance of 68Ga-PET at 1 h p.i. but has advantages in late-time imaging at 4 h p.i., as it provides improved tumor-to-non-tumor ratios. [61Cu]Cu-NODAGA-TOC is superior to [61Cu]Cu-DOTA-TOC in vivo. The use of the chelator NODAGA allows quantitative labeling with copper-61 at room temperature and enables the straightforward use of a kit formulation for simple manufacturing in medical centers.

铜-61 是体生长抑素受体表达肿瘤 PET 成像中镓-68 的优势替代品:一项头对头临床前比较研究。
背景:镓-68正电子发射断层扫描(68Ga-PET)使用两种注册的体生长激素类似物,即[68Ga]Ga-DOTA-Tyr3-octreotide([68Ga]Ga-DOTA-TOC)和[68Ga]Ga-DOTA-Tyr3-octreotate([68Ga]Ga-DOTA-TATE)、其中 DOTA = 1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸,被常规用于表达体生长抑素受体(SST)的肿瘤成像。我们研究了铜-61(61Cu),将其作为表达 SST 的肿瘤 PET 成像的替代放射性金属。与镓-68相比,铜-61(t1/2 = 3.33 h,E β + max = 1.22 MeV)可以大规模生产,可以进行晚期时间点成像,并且具有治疗孪生铜-67的特性。在此,我们用铜-61标记了DOTA-TOC和1,4,7-三氮杂环壬烷,1-戊二酸-4,7-乙酸(NODAGA)-TOC,并与临床使用的[68Ga]Ga-DOTA-TOC进行了比较。在醋酸铵缓冲液中用[61Cu]CuCl2标记DOTA-TOC和NODAGA-TOC,使反应pH值达到5-6,DOTA-TOC的反应温度为95°C,NODAGA-TOC的反应温度为室温。利用人体胚胎肾(HEK)-SST2 细胞(亲和力、结合位点、细胞摄取和外流)和 HEK-SST2 异种移植物(体内)[PET/计算机断层扫描(CT)成像、生物分布和药代动力学]对这些放射性配体进行了正面评估,并与采用标准程序制备的[68Ga]Ga-DOTA-TOC 进行了比较。对[61Cu]Cu-NODAGA-TOC进行了剂量估算:结果:[61Cu]Cu-DOTA-TOC 和 [61Cu]Cu-NODAGA-TOC 的表观摩尔活度为 25 MBq/nmol,放射化学纯度分别为≥96%和≥98%。在体外,这两种药物对 SST2 的亲和力都在纳摩尔以下(IC50 = 0.23 和 0.34 nM)。它们与表达 SST2 的细胞结合后几乎完全内化,在 37°C 时的外流率相似。在体内,[61Cu]Cu-DOTA-TOC 和[61Cu]Cu-NODAGA-TOC 在表达 SST2 的肿瘤中显示出相同的蓄积。然而,PET/CT 图像和生物分布分析清楚地表明,[61Cu]Cu-DOTA-TOC 的生物分布不利,其特点是在肝脏和腹部聚集。[61Cu]Cu-NODAGA-TOC显示出良好的生物分布,在注射后1小时与[68Ga]Ga-DOTA-TOC相当。尽管如此,[61Cu]Cu-NODAGA-TOC在注射后4小时仍显示出优势,这是因为肿瘤保留率和肿瘤与非肿瘤的比率得到了改善。61Cu]Cu-NODAGA-TOC的有效剂量(2.41×10-3 mSv/MBq)以及其他器官和肾脏的剂量(9.65×10-2 mGy/MBq)都表明其安全性良好:结论:61Cu-PET 成像不仅能与 68Ga-PET 在 1 小时内的成像效果相媲美,而且在 4 小时内的晚期成像中也具有优势,因为它能提高肿瘤与非肿瘤的比例。在体内,[61Cu]Cu-NODAGA-TOC优于[61Cu]Cu-DOTA-TOC。使用螯合剂 NODAGA 可以在室温下对铜-61 进行定量标记,并能直接使用试剂盒配方,方便医疗中心的生产。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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