Radford Lauren, Gallazzi Fabio, Watkinson Lisa, Carmack Terry, Berendzen Ashley, Lewis Michael R, Jurisson Silvia S, Papagiannopoulou Dionysia, Hennkens Heather M
Department of Chemistry, University of Missouri, Columbia, MO 65211, USA.
Structural Biology Core, University of Missouri, Columbia, MO 65211, USA.
Nucl Med Biol. 2017 Apr;47:4-9. doi: 10.1016/j.nucmedbio.2016.12.002. Epub 2016 Dec 9.
A somatostatin receptor (SSTR)-targeting antagonist peptide (sst-ANT) was radiolabeled with Tc tricarbonyl via a tridentate [N,S,N]-type ligand (L) to develop a radiodiagnostic agent, TcL-sst-ANT, for imaging of SSTR-expressing neuroendocrine tumors.
Receptor affinity was assessed in vitro with the nonradioactive analogue, ReL-sst-ANT, via a challenge experiment in AR42J cells with I-SS-14 as the competing radioligand. Preparation of TcL-sst-ANT was achieved via reaction of [Tc(CO)(HO)] with L-sst-ANT. To test the stability of the radiolabeled complex, challenge experiments were performed in phosphate-buffered saline solutions containing cysteine or histidine and also in mouse serum. Biodistribution and micro-SPECT/CT imaging studies were performed in AR42J tumor-bearing female ICR SCID mice.
The half maximal inhibitory concentration (IC value) of ReL-sst-ANT in AR42J cells was 15nM. Preparation of TcL-sst-ANT was achieved with ≥97% radiochemical yield (RCY) and was verified by HPLC co-elution with the ReL-sst-ANT analogue. The radiolabeled complex remained intact for up to 24h in high concentration solutions of cysteine and histidine at 37°C. Furthermore, the radiotracer was 90% stable for 1h at 37°C in mouse serum. Micro-SPECT/CT images showed clear uptake in tumors and were supported by the biodistribution data, in which the 3.2% ID/g tumor uptake at 4h was significantly blocked by co-administration of nonradioactive SS-14.
A [Tc(CO)(N,S,N)] chelate was employed for radiolabeling of an SSTR-targeting antagonist peptide. Synthesis of TcL-sst-ANT was achieved in high RCY, and the resulting complex displayed high in vitro stability. Somatostatin receptor affinity was retained in both cells and in tumor-bearing mice, where the complex successfully targeted SSTR-positive tumors via a receptor-mediated process. Advances in Knowledge and Implications for Patient Care. This first Tc-tricarbonyl-labeled SSTR antagonist peptide showed promising in vivo tumor targeting in mice. Future studies may lead to translation of a similar design into the clinic.
一种靶向生长抑素受体（SSTR）的拮抗剂肽（sst-ANT）通过三齿[N,S,N]型配体（L）用三羰基锝进行放射性标记，以开发一种用于成像表达SSTR的神经内分泌肿瘤的放射性诊断剂TcL-sst-ANT。
通过在AR42J细胞中以I-SS-14作为竞争放射性配体的竞争实验，用非放射性类似物ReL-sst-ANT在体外评估受体亲和力。通过[Tc(CO)(HO)]与L-sst-ANT反应制备TcL-sst-ANT。为了测试放射性标记复合物的稳定性，在含有半胱氨酸或组氨酸的磷酸盐缓冲盐溶液以及小鼠血清中进行竞争实验。在携带AR42J肿瘤的雌性ICR SCID小鼠中进行生物分布和微型SPECT/CT成像研究。
ReL-sst-ANT在AR42J细胞中的半数最大抑制浓度（IC值）为15nM。以≥97%的放射化学产率（RCY）制备了TcL-sst-ANT，并通过与ReL-sst-ANT类似物的HPLC共洗脱进行了验证。在37°C下，放射性标记的复合物在半胱氨酸和组氨酸的高浓度溶液中长达24小时保持完整。此外，放射性示踪剂在37°C下于小鼠血清中1小时内90%稳定。微型SPECT/CT图像显示肿瘤中有明显摄取，生物分布数据也支持这一点，其中在4小时时3.2%ID/g的肿瘤摄取被共同给予非放射性SS-14显著阻断。
一种[Tc(CO)(N,S,N)]螯合物用于靶向SSTR的拮抗剂肽的放射性标记。以高RCY实现了TcL-sst-ANT的合成，所得复合物显示出高体外稳定性。生长抑素受体亲和力在细胞和携带肿瘤的小鼠中均得以保留，其中该复合物通过受体介导的过程成功靶向SSTR阳性肿瘤。知识进展及对患者护理的意义。这种首个三羰基锝标记的SSTR拮抗剂肽在小鼠体内显示出有前景的肿瘤靶向性。未来的研究可能会将类似设计转化到临床应用中。
