School of Chemistry, The University of Melbourne, Parkville, VIC, Australia.
Dalton Trans. 2014 Jan 21;43(3):1386-96. doi: 10.1039/c3dt52647j. Epub 2013 Nov 7.
The use of copper radioisotopes in cancer diagnosis and radionuclide therapy is possible using chelators that are capable of binding Cu(II) with sufficient stability in vivo to provide high tumour-to-background contrast. Here we report the design and synthesis of a new bifunctional chelator, 5-(8-methyl-3,6,10,13,16,19-hexaaza-bicyclo[6.6.6]icosan-1-ylamino)-5-oxopentanoic acid (MeCOSar), that forms copper complexes of exceptional stability by virtue of a cage amine (sarcophagine) ligand and a new conjugate referred to as SarTATE, obtained by the conjugation of MeCOSar to the tumour-targeting peptide Tyr(3)-octreotate. Radiolabeling of SarTATE with (64)Cu(II), a radioisotope suitable for positron emission tomography (PET), was fast (~20 min), easily performed at room temperature and consistently resulted in high radiochemical purity (>99%). In vitro and in vivo evaluation of (64)CuSarTATE demonstrated its high selectivity for tumour cells expressing somatostatin receptor 2 (sstr2). Biodistribution and PET imaging comparisons were made between (64)CuSarTATE and (64)Cu-labeled DOTA-Tyr(3)-octreotate ((64)CuDOTATATE). Both radiopharmaceuticals showed excellent uptake in sstr2-positive tumours at 2 h post-injection. While tumour uptake of (64)CuDOTATATE decreased significantly at 24 h, (64)CuSarTATE activity was retained, improving contrast at later time points. (64)CuSarTATE accumulated less than (64)CuDOTATATE in the non-target organs, liver and lungs. The uptake of (64)CuSarTATE in the kidneys was high at 2 h but showed significant clearance by 24 h. The new chemistry and pre-clinical evaluation presented here demonstrates that MeCOSar is a promising bifunctional chelator for Tyr(3)-octreotate that could be applied to a combined imaging and therapeutic regimen using a combination of (64)Cu- and (67)CuSarTATE complexes, owing to improved tumour-to-non-target organ ratios compared to (64)CuDOTATATE at longer time points.
铜放射性同位素在癌症诊断和放射性核素治疗中的应用是可能的，使用能够在体内与 Cu(II) 结合足够稳定的螯合剂，以提供高肿瘤与背景的对比度。在这里，我们报告了一种新的双功能螯合剂的设计和合成，5-(8-甲基-3,6,10,13,16,19-六氮杂双环[6.6.6]二十烷-1-基氨基)-5-氧戊酸(MeCOSar)，通过笼状胺（sarcophagine）配体和一种新的共轭物 SarTATE 的结合，形成铜配合物的稳定性异常，SarTATE 是通过 MeCOSar 与肿瘤靶向肽 Tyr(3)-奥曲肽的结合得到的。放射性同位素（64）Cu(II)的放射性标记，一种适合正电子发射断层扫描（PET）的放射性同位素，速度很快（约 20 分钟），在室温下很容易进行，并且始终产生高放射化学纯度（>99%）。（64）CuSarTATE 的体外和体内评价表明，它对表达生长抑素受体 2（sstr2）的肿瘤细胞具有高选择性。在（64）CuSarTATE 和（64）Cu 标记的 DOTA-Tyr(3)-奥曲肽（（64）CuDOTATATE）之间进行了生物分布和 PET 成像比较。两种放射性药物在注射后 2 小时均在 sstr2 阳性肿瘤中显示出优异的摄取。虽然（64）CuDOTATATE 在 24 小时时肿瘤摄取显著减少，但（64）CuSarTATE 的活性得以保留，在后期时间点提高了对比度。（64）CuSarTATE 在非靶器官，肝脏和肺部中的积累低于（64）CuDOTATATE。（64）CuSarTATE 在肾脏中的摄取在 2 小时时很高，但在 24 小时时已显著清除。这里呈现的新化学和临床前评价表明，MeCOSar 是一种有前途的 Tyr(3)-奥曲肽双功能螯合剂，由于与（64）CuDOTATATE 相比，在更长的时间点，（64）Cu-和（67）CuSarTATE 配合物的组合在肿瘤与非靶器官比值方面的改善，可应用于联合成像和治疗方案。
