Recently, 44Sc (T1/2 = 3.97 h, Eβ+ av = 632 keV, I = 94.3 %) has emerged as an attractive radiometal candidate for PET imaging using DOTA-functionalized biomolecules. The aim of this study was to investigate the potential of using NODAGA for the coordination of 44Sc. Two pairs of DOTA/NODAGA-derivatized peptides were investigated in vitro and in vivo and the results obtained with 44Sc compared with its 68Ga-labeled counterparts. DOTA-RGD and NODAGA-RGD, as well as DOTA-NOC and NODAGA-NOC, were labeled with 44Sc and 68Ga, respectively. The radiopeptides were investigated with regard to their stability in buffer solution and under metal challenge conditions using Fe3+ and Cu2+. Time-dependent biodistribution studies and PET/CT imaging were performed in U87MG and AR42J tumor-bearing mice. Both RGD- and NOC-based peptides with a DOTA chelator were readily labeled with 44Sc and 68Ga, respectively, and remained stable over at least 4 half-lives of the corresponding radionuclide. In contrast, the labeling of NODAGA-functionalized peptides with 44Sc was more challenging and the resulting radiopeptides were clearly less stable than the DOTA-derivatized matches. 44Sc-NODAGA peptides were clearly more susceptible to metal challenge than 44Sc-DOTA peptides under the same conditions. Instability of 68Ga-labeled peptides was only observed if they were coordinated with a DOTA in the presence of excess Cu2+. Biodistribution data of the 44Sc-labeled peptides were largely comparable with the data obtained with the 68Ga-labeled counterparts. It was only in the liver tissue that the uptake of 68Ga-labeled DOTA compounds was markedly higher than for the 44Sc-labeled version and this was also visible on PET/CT images. The 44Sc-labeled NODAGA-peptides showed a similar tissue distribution to those of the DOTA peptides without any obvious signs of in vivo instability. Although DOTA revealed to be the preferred chelator for stable coordination of 44Sc, the data presented in this work indicate the possibility of using NODAGA in combination with 44Sc. In view of a clinical study, thorough investigations will be necessary regarding the labeling conditions and storage solutions in order to guarantee sufficient stability of 44Sc-labeled NODAGA compounds.

中文翻译：

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用于标记 DOTA 和 NODAGA 功能化肽的 44Sc：临床前体外和体内研究。

最近，44Sc（T1/2 = 3.97 h，Eβ+ av = 632 keV，I = 94.3 %）已成为使用 DOTA 功能化生物分子进行 PET 成像的有吸引力的放射性金属候选物。本研究的目的是调查使用 NODAGA 协调 44Sc 的潜力。在体外和体内研究了两对 DOTA/NODAGA 衍生肽，并将 44Sc 获得的结果与其 68Ga 标记的对应物进行了比较。DOTA-RGD 和 NODAGA-RGD，以及 DOTA-NOC 和 NODAGA-NOC，分别用 44Sc 和 68Ga 标记。研究了放射性肽在缓冲溶液中和使用 Fe3+ 和 Cu2+ 的金属挑战条件下的稳定性。在 U87MG 和 AR42J 荷瘤小鼠中进行时间依赖性生物分布研究和 PET/CT 成像。具有 DOTA 螯合剂的基于 RGD 和 NOC 的肽都容易分别用 44Sc 和 68Ga 标记，并且在相应放射性核素的至少 4 个半衰期内保持稳定。相比之下，用 44Sc 标记 NODAGA 功能化肽更具挑战性，并且由此产生的放射性肽明显不如 DOTA 衍生匹配稳定。在相同条件下，44Sc-NODAGA 肽明显比 44Sc-DOTA 肽更容易受到金属攻击。只有在过量 Cu2+ 存在下与 DOTA 配位时，才会观察到 68Ga 标记肽的不稳定性。44Sc 标记肽的生物分布数据在很大程度上与用 68Ga 标记对应物获得的数据相当。仅在肝组织中，68Ga 标记的 DOTA 化合物的摄取明显高于 44Sc 标记的版本，这在 PET/CT 图像上也可见。44Sc 标记的 NODAGA 肽显示出与 DOTA 肽相似的组织分布，没有任何明显的体内不稳定迹象。尽管 DOTA 显示是 44Sc 稳定配位的首选螯合剂，但这项工作中提供的数据表明 NODAGA 与 44Sc 结合使用的可能性。鉴于临床研究，需要对标记条件和储存溶液进行彻底调查，以保证 44Sc 标记的 NODAGA 化合物具有足够的稳定性。44Sc 标记的 NODAGA 肽显示出与 DOTA 肽相似的组织分布，没有任何明显的体内不稳定迹象。尽管 DOTA 显示是 44Sc 稳定配位的首选螯合剂，但这项工作中提供的数据表明 NODAGA 与 44Sc 结合使用的可能性。鉴于临床研究，需要对标记条件和储存溶液进行彻底调查，以保证 44Sc 标记的 NODAGA 化合物具有足够的稳定性。44Sc 标记的 NODAGA 肽显示出与 DOTA 肽相似的组织分布，没有任何明显的体内不稳定迹象。尽管 DOTA 显示是 44Sc 稳定配位的首选螯合剂，但这项工作中提供的数据表明 NODAGA 与 44Sc 结合使用的可能性。鉴于临床研究，需要对标记条件和储存溶液进行彻底调查，以保证 44Sc 标记的 NODAGA 化合物具有足够的稳定性。