School of Health Sciences, Purdue University, West Lafayette, IN 47907, USA.
Eur J Nucl Med Mol Imaging. 2009 Nov;36(11):1874-84. doi: 10.1007/s00259-009-1166-1. Epub 2009 May 30.
This report presents the synthesis of a cyclic RGD dimer conjugate, MAG(2)-G(3)-EG(3)-c(RGDfK) (MAG(2)-3G(3)-dimer, G(3) = Gly-Gly-Gly, MAG(2) = S-benzoyl mercaptoacetylglycylglycyl), and evaluation of its (99m)Tc complex, (99m)TcO(MAG(2)-3G(3)-dimer), as a new radiotracer for imaging the tumor integrin alpha(v)beta(3) expression.
An in vitro displacement assay was used to determine the integrin alpha(v)beta(3) binding affinity of MAG(2)-3G(3)-dimer against (125)I-c(RGDyK) bound to U87MG human glioma cells. The athymic nude mice bearing U87MG glioma xenografts were used for biodistribution and planar imaging studies.
We found that (1) MAG(2) is such a highly effective bifunctional chelator that (99m)TcO(MAG(2)-3G(3)-dimer) can be prepared in high yield (radiochemical purity >95%) and with high specific activity ( approximately 5 Ci/micromol) using a kit formulation; (2) (99m)TcO(MAG(2)-3G(3)-dimer) has very high solution stability in the kit matrix; and (3) (99m)TcO(MAG(2)-3G(3)-dimer) has very fast clearance kinetics from the intestine, liver, and kidneys. Among the (99m)Tc-labeled cyclic RGD peptides evaluated in the xenografted U87MG glioma models, (99m)TcO(MAG(2)-3G(3)-dimer) has the best pharmacokinetics and tumor to background ratios (tumor/liver = 4.29 +/- 1.00 at 30 min postinjection and 8.29 +/- 1.50 at 120 min postinjection; tumor/kidney = 1.16 +/- 0.19 at 30 min postinjection and 2.49 +/- 0.25 at 120 min postinjection). Planar imaging studies showed that tumors in the glioma-bearing mice administered with (99m)TcO(MAG(2)-3G(3)-dimer) can be visualized with excellent contrast as early as 15 min postinjection. (99m)TcO(MAG(2)-3G(3)-dimer) was able to maintain its chemical integrity in kidneys (>80% intact) and liver (>95% intact) over the 2-h period. However, there was significant metabolism (>50% of the injected radioactivity) detected in both urine and feces samples.
(99m)TcO(MAG(2)-3G(3)-dimer) is a very attractive radiotracer for early detection of integrin alpha(v)beta(3)-positive tumors and has significant advantages over the (18)F-labeled RGD peptide radiotracers with respect to the cost, availability, and easiness for routine clinical preparation.
本报告介绍了一种环状 RGD 二聚体缀合物 MAG(2)-G(3)-E[G(3)-c(RGDfK)]（2）（MAG(2)-3G(3)-二聚体，G(3)=甘氨酰-甘氨酰-甘氨酸，MAG(2)=S-苯甲酰巯基乙酰甘氨酰甘氨酸）的合成，并评估了其（99m）Tc 络合物（99m）TcO（MAG(2)-3G(3)-二聚体）作为一种新的放射性示踪剂，用于成像肿瘤整合素 alpha(v)beta(3)表达。
采用体外置换试验测定 MAG(2)-3G(3)-二聚体与（125）I-c（RGDyK）结合的 U87MG 人神经胶质瘤细胞的整合素 alpha(v)beta(3)结合亲和力。荷 U87MG 神经胶质瘤异种移植瘤的裸鼠用于生物分布和平面成像研究。
我们发现：（1）MAG(2)是一种非常有效的双功能螯合剂，可在试剂盒制剂中以高产率（放射性化学纯度>95%）和高比活度（约 5 Ci/μmol）制备（99m）TcO（MAG(2)-3G(3)-二聚体）；（2）（99m）TcO（MAG(2)-3G(3)-二聚体）在试剂盒基质中具有非常高的溶液稳定性；（3）（99m）TcO（MAG(2)-3G(3)-二聚体）从肠道、肝脏和肾脏中的清除动力学非常快。在所评估的用于异种移植 U87MG 神经胶质瘤模型的（99m）Tc 标记的环状 RGD 肽中，（99m）TcO（MAG(2)-3G(3)-二聚体）具有最佳的药代动力学和肿瘤与背景比值（注射后 30 分钟时肿瘤/肝脏为 4.29±1.00，120 分钟时为 8.29±1.50；注射后 30 分钟时肿瘤/肾脏为 1.16±0.19，120 分钟时为 2.49±0.25）。平面成像研究表明，注射（99m）TcO（MAG(2)-3G(3)-二聚体）的荷瘤小鼠的肿瘤在注射后 15 分钟即可通过极好的对比度进行可视化。（99m）TcO（MAG(2)-3G(3)-二聚体）在 2 小时内可在肾脏（>80%完整）和肝脏（>95%完整）中保持其化学完整性。然而，在尿液和粪便样本中均检测到显著的代谢物（>50%的放射性标记物）。
（99m）TcO（MAG(2)-3G(3)-二聚体）是一种非常有吸引力的用于早期检测整合素 alpha(v)beta(3)阳性肿瘤的放射性示踪剂，与（18）F 标记的 RGD 肽放射性示踪剂相比，在成本、可用性和常规临床制备的简易性方面具有显著优势。
