Domnanich Katharina A, Müller Cristina, Farkas Renata, Schmid Raffaella M, Ponsard Bernard, Schibli Roger, Türler Andreas, van der Meulen Nicholas P
Laboratory of Radiochemistry, Paul Scherrer Institute, CH-5232 Villigen-PSI, Switzerland.
Department of Chemistry and Biochemistry, University of Bern, 3012 Bern, Switzerland.
EJNMMI Radiopharm Chem. 2017;1(1):8. doi: 10.1186/s41181-016-0013-5. Epub 2016 May 5.
Recently, Sc (T = 3.97 h, Eβ = 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 Sc. Two pairs of DOTA/NODAGA-derivatized peptides were investigated in vitro and in vivo and the results obtained with Sc compared with its Ga-labeled counterparts.DOTA-RGD and NODAGA-RGD, as well as DOTA-NOC and NODAGA-NOC, were labeled with Sc and Ga, respectively. The radiopeptides were investigated with regard to their stability in buffer solution and under metal challenge conditions using Fe and Cu. 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 Sc and Ga, respectively, and remained stable over at least 4 half-lives of the corresponding radionuclide. In contrast, the labeling of NODAGA-functionalized peptides with Sc was more challenging and the resulting radiopeptides were clearly less stable than the DOTA-derivatized matches. Sc-NODAGA peptides were clearly more susceptible to metal challenge than Sc-DOTA peptides under the same conditions. Instability of Ga-labeled peptides was only observed if they were coordinated with a DOTA in the presence of excess Cu. Biodistribution data of the Sc-labeled peptides were largely comparable with the data obtained with the Ga-labeled counterparts. It was only in the liver tissue that the uptake of Ga-labeled DOTA compounds was markedly higher than for the Sc-labeled version and this was also visible on PET/CT images. The Sc-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 Sc, the data presented in this work indicate the possibility of using NODAGA in combination with Sc. 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 Sc-labeled NODAGA compounds.
最近，钪（T = 3.97小时，Eβ = 632keV，I = 94.3%）已成为一种有吸引力的放射性金属候选物，可用于使用DOTA功能化生物分子的PET成像。本研究的目的是研究使用NODAGA进行钪配位的潜力。在体外和体内研究了两对DOTA/NODAGA衍生的肽，并将钪标记的结果与其镓标记的对应物进行比较。DOTA-RGD和NODAGA-RGD，以及DOTA-NOC和NODAGA-NOC分别用钪和镓进行标记。使用铁和铜，研究了放射性肽在缓冲溶液中和金属挑战条件下的稳定性。在U87MG和AR42J荷瘤小鼠中进行了时间依赖性生物分布研究和PET/CT成像。
带有DOTA螯合剂的基于RGD和NOC的肽分别很容易用钪和镓进行标记，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，用钪标记NODAGA功能化的肽更具挑战性，并且所得放射性肽明显比DOTA衍生的对应物稳定性差。在相同条件下，钪-NODAGA肽比钪-DOTA肽更容易受到金属挑战。仅当镓标记的肽在过量铜存在下与DOTA配位时，才观察到其不稳定性。钪标记肽的生物分布数据与镓标记对应物获得的数据在很大程度上具有可比性。仅在肝脏组织中，镓标记的DOTA化合物的摄取明显高于钪标记的版本，这在PET/CT图像上也可见。钪标记的NODAGA肽显示出与DOTA肽相似的组织分布，没有任何体内不稳定性的明显迹象。
尽管DOTA被证明是钪稳定配位的首选螯合剂，但本研究中给出的数据表明将NODAGA与钪联合使用的可能性。鉴于一项临床研究，有必要对标记条件和储存溶液进行全面研究，以确保钪标记的NODAGA化合物具有足够的稳定性。
