Pujatti P B, Santos J S, Couto R M, Melero L T U H, Suzuki M F, Soares C R J, Grallert S R M, Mengatti J, De Araújo E B
Radiopharmacy Directory, Nuclear and Energy Research Institute (IPEN/CNEN), São Paulo, Brazil.
Q J Nucl Med Mol Imaging. 2011 Jun;55(3):310-23.
Bombesin (BBN) has demonstrated the ability to bind with high affinity and specificity to GRP receptor, overexpressed on human prostate cancer. A large number of BBN derivatives have been synthesized for this purpose but most of them exhibit high abdominal accumulation, which may represent a problem in their clinical use due to serious side effects to patients. In this study we describe the results of radiolabeling with lutetium-177, stability and in vivo studies of novel phenyl-glycine-extended bombesin derivatives. The spacers were inserted to improve bombesin in vivo properties and to reduce its target to non-tumor sites.
Preliminary studies were done to establish the ideal conditions for labeling bombesin derivatives. Chromatography systems were applied to determine free lutetium and the stability of the preparations was evaluated either after storing at 2-8 ºC or incubation in human serum at 37 ºC. In vivo experiments included biodistribution, pharmacokinetics and SPECT images and were performed in Balb-c and Nude mice bearing PC-3 xenografts.
The derivatives were labeled with high yield and kept stable at 2-8 ºC and are metabolized by human serum enzymes. In vivo studies showed fast blood clearance of labeled peptides and rapid excretion, performed mainly by renal pathway. In addition, biodistribution and imaging studies showed low abdominal accumulation and significant and specific tumor uptake of (177)Lu-labeled derivatives.
The derivative with longer spacer holds a higher potential as radiopharmaceutical for prostate tumor diagnosis and the derivatives with shorter spacers are potential radiopharmaceuticals for prostate tumor treatment.
蛙皮素（BBN）已证明能以高亲和力和特异性与在人类前列腺癌中过度表达的胃泌素释放肽（GRP）受体结合。为此已合成了大量的BBN衍生物，但其中大多数在腹部有较高的蓄积，由于对患者有严重的副作用，这可能在其临床应用中成为一个问题。在本研究中，我们描述了新型苯基 - 甘氨酸延伸的蛙皮素衍生物用镥 - 177进行放射性标记及其稳定性和体内研究的结果。插入间隔基团以改善蛙皮素的体内性质，并减少其在非肿瘤部位的靶向性。
进行初步研究以确定标记蛙皮素衍生物的理想条件。应用色谱系统测定游离镥，并在2 - 8℃储存后或在37℃的人血清中孵育后评估制剂的稳定性。体内实验包括生物分布、药代动力学和单光子发射计算机断层扫描（SPECT）图像，并在携带PC - 3异种移植物的Balb - c和裸鼠中进行。
衍生物以高产率标记，在2 - 8℃保持稳定，并被人血清酶代谢。体内研究表明标记肽的血液清除迅速且排泄迅速，主要通过肾脏途径进行。此外，生物分布和成像研究表明，（177）Lu标记的衍生物腹部蓄积低，肿瘤摄取显著且具有特异性。
间隔基团较长的衍生物作为前列腺肿瘤诊断的放射性药物具有更高的潜力，而间隔基团较短的衍生物是前列腺肿瘤治疗的潜在放射性药物。
