Mallinckrodt Institute of Radiology, Washington University, St. Louis, MO, USA.
Bioconjug Chem. 2012 Jul 18;23(7):1470-7. doi: 10.1021/bc300092n. Epub 2012 Jun 18.
Somatostatin receptors (SSTr) are overexpressed in a wide range of neuroendocrine tumors, making them excellent targets for nuclear imaging and therapy, and radiolabeled somatostatin analogues have been investigated for positron emission tomography imaging and radionuclide therapy of SSTr-positive tumors, especially of the subtype-2 (SSTr2). The aim of this study was to develop a somatostatin analogue, Tyr(3)-octreotate (Y3-TATE), conjugated to a novel cross-bridged macrocyclic chelator, 11-carboxymethyl-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane-4-methanephosphonic acid (CB-TE1A1P). Unlike traditional cross-bridged macrocycles, such as 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (CB-TE2A), CB-TE1A1P-Y3-TATE was radiolabeled with (64)Cu in high purity and high specific activity using mild conditions. Saturation binding assays revealed that (64)Cu-CB-TE1A1P-Y3-TATE had comparable binding affinity but bound to more binding sites in AR42J rat pancreatic tumor cell membranes than (64)Cu-CB-TE2A-Y3-TATE. Both radiopharmaceuticals showed comparable uptake in SSTr2 positive tissues in AR42J tumor-bearing rats. (64)Cu-CB-TE1A1P-Y3-TATE demonstrated improved blood clearance compared to (64)Cu-CB-TE2A-Y3-TATE, as the tumor/blood ratios of (64)Cu-CB-TE1A1P-Y3-TATE were shown to be significantly higher than those of (64)Cu-CB-TE2A-Y3-TATE at 4 and 24 h postinjection. (64)Cu-CB-TE1A1P-Y3-TATE, in spite of a relatively high kidney uptake, accumulated less in nontarget organs such as liver, lung, and bone. Small animal PET/CT imaging of (64)Cu-CB-TE1A1P-Y3-TATE in AR42J tumor bearing rats validated significant uptake and good contrast in the tumor. This study suggests that CB-TE1A1P is a promising bifunctional chelator for (64)Cu-labeled for Y3-TATE, owing to high binding affinity and target tissue uptake, the ability to radiolabel the agent at lower temperatures, and improved tumor/nontarget organ ratios over (64)Cu-CB-TE2A-Y3-TATE.
生长抑素受体（SSTr）在广泛的神经内分泌肿瘤中过度表达，使其成为核成像和治疗的理想靶点，放射性标记的生长抑素类似物已被用于 SSTr 阳性肿瘤的正电子发射断层扫描成像和放射性核素治疗，尤其是 SSTr-2 型（SSTr2）。本研究旨在开发一种生长抑素类似物，Tyr（3）-奥曲肽（Y3-TATE），与一种新型交联大环螯合剂 11-羧甲基-1,4,8,11-四氮杂环十六烷-4-甲膦酸（CB-TE1A1P）偶联。与传统的交联大环，如 4,11-双（羧甲基）-1,4,8,11-四氮杂环十六烷（CB-TE2A）不同，CB-TE1A1P-Y3-TATE 可以在温和的条件下用（64）Cu 进行高纯度和高比活度的放射性标记。饱和结合实验表明，（64）Cu-CB-TE1A1P-Y3-TATE 与 AR42J 大鼠胰腺肿瘤细胞膜上的结合位点具有相似的结合亲和力，但结合的结合位点比（64）Cu-CB-TE2A-Y3-TATE 多。两种放射性药物在 AR42J 荷瘤大鼠的 SSTR2 阳性组织中均表现出相似的摄取。与（64）Cu-CB-TE2A-Y3-TATE 相比，（64）Cu-CB-TE1A1P-Y3-TATE 的血液清除率得到改善，因为（64）Cu-CB-TE1A1P-Y3-TATE 的肿瘤/血液比值在注射后 4 小时和 24 小时明显高于（64）Cu-CB-TE2A-Y3-TATE。尽管（64）Cu-CB-TE1A1P-Y3-TATE 的肾脏摄取较高，但在非靶器官（如肝、肺和骨）中的摄取较少。AR42J 荷瘤大鼠的（64）Cu-CB-TE1A1P-Y3-TATE 小动物 PET/CT 成像证实了肿瘤中有明显的摄取和良好的对比。这项研究表明，CB-TE1A1P 是一种很有前途的双功能螯合剂，可用于（64）Cu 标记 Y3-TATE，因为其具有高结合亲和力和靶组织摄取能力，能够在较低温度下标记该药物，并且与（64）Cu-CB-TE2A-Y3-TATE 相比，肿瘤/非靶器官比值更高。
