Sprague Jennifer E, Peng Yijie, Sun Xiankai, Weisman Gary R, Wong Edward H, Achilefu Samuel, Anderson Carolyn J
Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Clin Cancer Res. 2004 Dec 15;10(24):8674-82. doi: 10.1158/1078-0432.CCR-04-1084.
Somatostatin receptors (SSTr) are expressed on many neuroendocrine tumors, and several radiotracers have been developed for imaging these types of tumors. For this reason, peptide analogues of somatostatin have been well characterized. Copper-64 (t(1/2) = 12.7 hours), a positron emitter suitable for positron emission tomography (PET) imaging, was shown recently to have improved in vivo clearance properties when chelated by the cross-bridged tetraazamacrocycle 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo(6.6.2)hexadecane (CB-TE2A) compared with 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA).
CB-TE2A and TETA were conjugated to the somatostatin analogue tyrosine-3-octreotate (Y3-TATE) for evaluation of CB-TE2A as a bifunctional chelator of 64Cu. The in vitro affinity of each compound for SSTr was determined using a homologous competitive binding assay. In vivo characteristics of both radiolabeled compounds were examined in biodistribution and microPET studies of AR42J tumor-bearing rats.
Cu-CB-TE2A-Y3-TATE (Kd = 1.7 nmol/L) and Cu-TETA-Y3-TATE (Kd = 0.7 nmol/L) showed similar affinities for AR42J derived SSTr. In biodistribution studies, nonspecific uptake in blood and liver was lower for 64Cu-CB-TE2A-Y3-TATE. Differences increased with time such that, at 4 hours, blood uptake was 4.3-fold higher and liver uptake was 2.4-fold higher for 64Cu-TETA-Y3-TATE than for 64Cu-CB-TE2A-Y3-TATE. In addition, 4.4-times greater tumor uptake was detected with 64Cu-CB-TE2A-Y3-TATE than with 64Cu-TETA-Y3-TATE at 4 hours postinjection. MicroPET imaging yielded similar results.
CB-TE2A appears to be a superior in vivo bifunctional chelator of 64Cu for use in molecular imaging by PET or targeted radiotherapy due to both improved nontarget organ clearance and higher target organ uptake of 64Cu-CB-TE2A-Y3-TATE compared with 64Cu-TETA-Y3-TATE.
生长抑素受体（SSTr）在许多神经内分泌肿瘤中表达，已开发出几种放射性示踪剂用于这类肿瘤的成像。因此，生长抑素的肽类似物已得到充分表征。铜 - 64（半衰期 = 12.7小时）是一种适用于正电子发射断层扫描（PET）成像的正电子发射体，最近研究表明，与1,4,8,11 - 四氮杂环十四烷 - 1,4,8,11 - 四乙酸（TETA）相比，当被交联四氮杂大环4,11 - 双（羧甲基）-1,4,8,11 - 四氮杂双环（6.6.2）十六烷（CB - TE2A）螯合时，其体内清除特性有所改善。
将CB - TE2A和TETA与生长抑素类似物酪氨酸 - 3 - 奥曲肽（Y3 - TATE）偶联，以评估CB - TE2A作为64Cu的双功能螯合剂。使用同源竞争结合试验测定每种化合物对SSTr的体外亲和力。在荷AR42J肿瘤大鼠的生物分布和微型PET研究中检查了两种放射性标记化合物的体内特性。
Cu - CB - TE2A - Y3 - TATE（解离常数Kd = 1.7 nmol/L）和Cu - TETA - Y3 - TATE（Kd = 0.7 nmol/L）对源自AR42J的SSTr表现出相似的亲和力。在生物分布研究中，64Cu - CB - TE2A - Y3 - TATE在血液和肝脏中的非特异性摄取较低。差异随时间增加，以至于在4小时时，64Cu - TETA - Y3 - TATE的血液摄取比64Cu - CB - TE2A - Y3 - TATE高4.3倍，肝脏摄取高2.4倍。此外，注射后4小时，64Cu - CB - TE2A - Y3 - TATE检测到的肿瘤摄取比64Cu - TETA - Y3 - TATE高4.4倍。微型PET成像产生了相似的结果。
与64Cu - TETA - Y3 - TATE相比，CB - TE2A似乎是一种用于PET分子成像或靶向放射治疗的64Cu的更优体内双功能螯合剂，因为64Cu - CB - TE2A - Y3 - TATE具有更好的非靶器官清除率和更高的靶器官摄取率。
