Breeman Wouter A P, de Jong Marion, Erion Jack L, Bugaj Joseph E, Srinivasan Ananth, Bernard Bert F, Kwekkeboom Dik J, Visser Theo J, Krenning Eric P
Department of Nuclear Medicine, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands.
J Nucl Med. 2002 Dec;43(12):1650-6.
The 14-amino-acid peptide bombesin (BN) has a high affinity for the gastrin-releasing peptide (GRP) receptor that is expressed by a variety of tumors. Recently, high densities of GRP receptors were identified by in vitro receptor autoradiography in human prostate and breast carcinomas using [(125)I-Tyr(4)]BN as radioligand. Radiometal-labeled diethylenetriaminepentaacetic acid (DTPA)-BN derivatives are potentially useful radioligands for receptor-targeted scintigraphy and radiotherapy of GRP receptor-expressing tumors.
[DTPA-Pro(1),Tyr(4)]BN (A), [DOTA-Pro(1),Tyr(4)]BN (B), [DTPA-epsilon-Lys(3),Tyr(4)]BN (C), and [DOTA-epsilon-Lys(3),Tyr(4)]BN (D) (where DOTA is dodecanetetraacetic acid) were synthesized and studied for competition with binding of [(125)I-Tyr(4)]BN to the GRP receptor. The (111)In-labeled BN analogs were studied in vitro for binding and internalization by GRP receptor-expressing CA20948 and AR42J pancreatic tumor cells as well as in vivo for tissue distribution in rats. Specific tissue binding was tested by coinjection of 0.1 mg [Tyr(4)]BN.
All BN analogs competitively inhibited the binding of [(125)I-Tyr(4)]BN to the GRP receptor with 50% inhibitory concentration values in the range of 2-9 nmol/L. All (111)In-labeled analogs showed high and specific time- and temperature-dependent binding and internalization by CA20948 and AR42J cells. In in vivo studies, high and specific binding was found in GRP receptor-positive tissues such as pancreas (0.90, 1.2, 0.54, and 0.79 percentage injected dose per gram for A-D, respectively). In a rat model, the AR42J tumor could clearly be visualized by scintigraphy using [(111)In-DTPA-Pro(1),Tyr(4)]BN as the radioligand. Although [(111)In-DOTA-Pro(1),Tyr(4)]BN showed the highest uptake of radioactivity in GRP receptor-positive tissues as well as higher target-to-blood ratios, [(111)In-DTPA-Pro(1),Tyr(4)]BN was easier to handle and is more practical to use. Therefore, we decided to start phase I studies with this DTPA-conjugated radioligand.
[(111)In-DTPA-Pro(1),Tyr(4)]BN is a promising radioligand for scintigraphy of GRP receptor-expressing tumors. We are currently performing a phase I study on patients with invasive prostate carcinoma.
14 个氨基酸的蛙皮素（BN）对多种肿瘤表达的胃泌素释放肽（GRP）受体具有高亲和力。最近，使用[(125)I-Tyr(4)]BN作为放射性配体，通过体外受体放射自显影在人前列腺癌和乳腺癌中鉴定出高密度的GRP受体。放射性金属标记的二乙三胺五乙酸（DTPA）-BN衍生物可能是用于GRP受体表达肿瘤的受体靶向闪烁扫描和放射治疗的有用放射性配体。
合成了[DTPA-Pro(1),Tyr(4)]BN（A）、[DOTA-Pro(1),Tyr(4)]BN（B）、[DTPA-ε-Lys(3),Tyr(4)]BN（C）和[DOTA-ε-Lys(3),Tyr(4)]BN（D）（其中DOTA是十二烷四乙酸），并研究了它们与[(125)I-Tyr(4)]BN与GRP受体结合的竞争情况。对(111)In标记的BN类似物进行体外研究，观察其与表达GRP受体的CA20948和AR42J胰腺肿瘤细胞的结合和内化情况，以及在大鼠体内的组织分布。通过共同注射0.1 mg [Tyr(4)]BN测试特异性组织结合。
所有BN类似物均竞争性抑制[(125)I-Tyr(4)]BN与GRP受体的结合，其50%抑制浓度值在2 - 9 nmol/L范围内。所有(111)In标记的类似物在CA20948和AR42J细胞中均表现出高度特异性的时间和温度依赖性结合及内化。在体内研究中，在GRP受体阳性组织如胰腺中发现了高度特异性结合（A - D分别为每克注射剂量的0.90%、1.2%、0.54%和0.79%）。在大鼠模型中，使用[(111)In-DTPA-Pro(1),Tyr(4)]BN作为放射性配体，通过闪烁扫描可以清晰地观察到AR42J肿瘤。尽管[(111)In-DOTA-Pro(1),Tyr(4)]BN在GRP受体阳性组织中显示出最高的放射性摄取以及更高的靶血比，但[(111)In-DTPA-Pro(1),Tyr(4)]BN更易于处理且使用更实际。因此，我们决定开始使用这种DTPA共轭放射性配体进行I期研究。
[(111)In-DTPA-Pro(1),Tyr(4)]BN是用于GRP受体表达肿瘤闪烁扫描的有前景的放射性配体。我们目前正在对侵袭性前列腺癌患者进行I期研究。
