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首页> 外文期刊>Dalton transactions: An international journal of inorganic chemistry >PET imaging of tumours with a ~(64)Cu labeled macrobicyclic cage amine ligand tethered to Tyr~3-octreotate
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PET imaging of tumours with a ~(64)Cu labeled macrobicyclic cage amine ligand tethered to Tyr~3-octreotate

机译：用〜（64）Cu标记的大双环笼胺配体与Tyr〜3-奥曲肽栓系的肿瘤的PET成像

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摘要

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 nontarget 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.
机译：使用能够在体内以足够的稳定性结合Cu〜（II）以提供高的肿瘤-背景对比的螯合剂，可以在癌症诊断和放射性核素治疗中使用铜放射性同位素。在这里，我们报告新型双功能螯合剂5-（8-甲基-3,6,10,13,16,19-六氮杂-双环[6.6.6] icosan-1-ylamino）-5-oxopentanoic的设计和合成酸（MeCOSar），通过笼型胺（石棺）配体和新的称为SarTATE的缀合物形成具有极高稳定性的铜络合物，该缀合物通过将MeCOSar与肿瘤靶向肽Tyr〜3-奥曲肽结合而获得。适用于正电子发射断层扫描（PET）的放射性同位素〜（64）Cu〜（II）对SarTATE进行放射性标记，快速（〜20分钟），在室温下容易进行，并始终导致高放射化学纯度（> 99％） 。 〜（64）CuSarTATE的体外和体内评估证明了其对表达生长抑素受体2（sstr2）的肿瘤细胞的高选择性。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 h对sstr2阳性肿瘤均具有良好的摄取。尽管〜（64）CuDOTATATE的肿瘤摄取在24 h显着降低，但〜（64）CuSarTATE活性得以保留，从而在以后的时间点改善了对比度。 〜（64）CuSarTATE在非目标器官，肝和肺中的累积量少于〜（64）CuDOTATATE。肾脏中〜（64）CuSarTATE的摄取在2小时时较高，但到24小时时显示出明显的清除率。此处介绍的新化学方法和临床前评估表明，MeCOSar是一种有前途的双功能螯合剂，用于Tyr〜3-奥曲肽，可通过〜（64）Cu-和〜（67）的组合应用于组合成像和治疗方案CuSarTATE复合物，由于在更长的时间点上与〜（64）CuDOTATATE相比，肿瘤与非目标器官的比率提高了。

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