Yang Yi-Shan, Zhang Xianzhong, Xiong Zhengming, Chen Xiaoyuan
Department of Radiology and Bio-X Program, The Molecular Imaging Program at Stanford (MIPS), Stanford University School of Medicine, Stanford, CA 94305-5484, USA.
Nucl Med Biol. 2006 Apr;33(3):371-80. doi: 10.1016/j.nucmedbio.2005.12.011. Epub 2006 Mar 9.
Bombesin (BBN), an analog of human gastrin-releasing peptide (GRP), binds to the GRP receptor (GRPR) with high affinity and specificity. Overexpression of GRPR has been discovered in mostly androgen-independent human prostate tissues and, thus, provides a potential target for prostate cancer diagnosis and therapy. We have previously demonstrated the feasibility of the positron emission tomography (PET) imaging using 64Cu-1,4,7,10-tetraazadodecane-N,N',N'',N'''-tetraacetic acid (DOTA)-[Lys3]BBN to detect GRPR-positive prostate cancer. In this study, we compared the receptor affinity, metabolic stability, tumor-targeting efficacy, and pharmacokinetics of a truncated BBN analog 64Cu-DOTA-Aca-BBN(7-14) with 64Cu-DOTA-[Lys3]BBN. Binding of each DOTA conjugate to GRPR on PC-3 and 22Rv1 prostate cancer cells was evaluated with competitive binding assay using 125I-[Tyr4]BBN as radioligand. In vivo pharmacokinetics was determined on male nude mice subcutaneously implanted with PC-3 cells. Dynamic microPET imaging was performed to evaluate the systemic distribution of the tracers. Metabolic stability of the tracers in blood, urine, tumor, liver and kidney was studied using high-performance liquid chromatography. The results showed that 125I-[Tyr4]BBN has a K(d) of 14.8+/-0.4 nM against PC-3 cells, and the receptor concentration on PC-3 cell surface is approximately 2.7+/-0.1 x 10(6) receptors per cell. The 50% inhibitory concentration value for DOTA-Aca-BBN(7-14) is 18.4 +/- 0.2 nM, and that for DOTA-[Lys3]BBN is 2.2 +/- 0.5 nM. DOTA-[Lys3]BBN shows a better tumor contrast and absolute tumor activity accumulation compared to DOTA-Aca-BBN(7-14). Studies on metabolic stability for both tracers on organ homogenates showed that 64Cu-DOTA-[Lys3]BBN is relatively stable. This study demonstrated that both tracers are suitable for targeted PET imaging to detect the expression of GRPR in prostate cancer, while 64Cu-DOTA-[Lys3]BBN may have a better potential for clinical translation.
蛙皮素（BBN）是一种人类胃泌素释放肽（GRP）类似物，能以高亲和力和特异性与GRP受体（GRPR）结合。已发现在大多数雄激素非依赖性人类前列腺组织中GRPR过表达，因此为前列腺癌的诊断和治疗提供了一个潜在靶点。我们之前已证明使用64Cu-1,4,7,10-四氮杂十二烷-N,N',N'',N'''-四乙酸（DOTA）-[Lys3]BBN进行正电子发射断层扫描（PET）成像检测GRPR阳性前列腺癌的可行性。在本研究中，我们比较了截短的BBN类似物64Cu-DOTA-Aca-BBN(7-14)与64Cu-DOTA-[Lys3]BBN的受体亲和力、代谢稳定性、肿瘤靶向效能和药代动力学。使用125I-[Tyr4]BBN作为放射性配体，通过竞争性结合试验评估每种DOTA偶联物与PC-3和22Rv1前列腺癌细胞上GRPR的结合。在皮下植入PC-3细胞的雄性裸鼠身上测定体内药代动力学。进行动态微型PET成像以评估示踪剂的全身分布。使用高效液相色谱法研究示踪剂在血液、尿液、肿瘤、肝脏和肾脏中的代谢稳定性。结果表明，125I-[Tyr4]BBN对PC-3细胞的解离常数（K(d)）为14.8±0.4 nM，PC-3细胞表面的受体浓度约为每细胞2.7±0.1×10(6)个受体。DOTA-Aca-BBN(7-14)的半数抑制浓度值为18.4±0.2 nM，DOTA-[Lys3]BBN的半数抑制浓度值为2.2±0.5 nM。与DOTA-Aca-BBN(7-14)相比，DOTA-[Lys3]BBN显示出更好的肿瘤对比度和绝对肿瘤活性积累。对两种示踪剂在器官匀浆中的代谢稳定性研究表明，64Cu-DOTA-[Lys3]BBN相对稳定。本研究表明，两种示踪剂均适用于靶向PET成像以检测前列腺癌中GRPR的表达，而64Cu-DOTA-[Lys3]BBN可能具有更好的临床转化潜力。
