Zhang Xianzhong, Cai Weibo, Cao Feng, Schreibmann Eduard, Wu Yun, Wu Joseph C, Xing Lei, Chen Xiaoyuan
Molecular Imaging Program at Stanford (MIPS), Department of Radiology and Bio-X Program, Stanford University School of Medicine, Stanford, California 94305-5484, USA.
J Nucl Med. 2006 Mar;47(3):492-501.
The gastrin-releasing peptide receptor (GRPR) is found to be overexpressed in a variety of human tumors. The aim of this study was to develop 18F-labeled bombesin analogs for PET of GRPR expression in prostate cancer xenograft models.
[Lys3]Bombesin ([Lys3]BBN) and aminocaproic acid-bombesin(7-14) (Aca-BBN(7-14)) were labeled with 18F by coupling the Lys3 amino group and Aca amino group, respectively, with N-succinimidyl-4-18F-fluorobenzoate (18F-SFB) under slightly basic condition (pH 8.5). Receptor-binding affinity of FB-[Lys3]BBN and FB-Aca-BBN(7-14) was tested in PC-3 human prostate carcinoma cells. Internalization and efflux of both radiotracers were also evaluated. Tumor-targeting efficacy and in vivo kinetics of both radiotracers were examined in male athymic nude mice bearing subcutaneous PC-3 tumors by means of biodistribution and dynamic microPET imaging studies. 18F-FB-[Lys3]BBN was also tested for orthotopic PC-3 tumor delineation. Metabolic stability of 18F-FB-[Lys3]BBN was determined in mouse blood, urine, liver, kidney, and tumor homogenates at 1 h after injection.
The typical decay-corrected radiochemical yield was about 30%-40% for both tracers, with a total reaction time of 150 +/- 20 min starting from 18F-. 18F-FB-[Lys3]BBN had moderate stability in the blood and PC-3 tumor, whereas it was degraded rapidly in the liver, kidneys, and urine. Both radiotracers exhibited rapid blood clearance. 18F-FB-[Lys3]BBN had predominant renal excretion. 18F-FB-Aca-BBN(7-14) exhibited both hepatobiliary and renal clearance. Dynamic microPET imaging studies revealed that the PC-3 tumor uptake of 18F-FB-[Lys3]BBN in PC-3 tumor was much higher than that of 18F-FB-Aca-BBN(7-14) at all time points examined (P < 0.01). The receptor specificity of 18F-FB-[Lys3]BBN in vivo was demonstrated by effective blocking of tumor uptake in the presence of [Tyr4]BBN. No obvious blockade was found in PC-3 tumor when 18F-FB-Aca-BBN(7-14) was used as radiotracer under the same condition. 18F-FB-[Lys3]BBN was also able to visualize orthotopic PC-3 tumor at early time points after tracer administration, at which time minimal urinary bladder activity was present to interfere with the receptor-mediated tumor uptake.
This study demonstrates that 18F-FB-[Lys3]BBN and PET are suitable for detecting GRPR-positive prostate cancer in vivo.
胃泌素释放肽受体（GRPR）在多种人类肿瘤中过度表达。本研究的目的是开发用于前列腺癌异种移植模型中GRPR表达PET成像的18F标记的蛙皮素类似物。
[Lys3]蛙皮素（[Lys3]BBN）和氨基己酸 - 蛙皮素（7 - 14）（Aca - BBN(7 - 14)）分别通过在弱碱性条件（pH 8.5）下将Lys3氨基和Aca氨基与N - 琥珀酰亚胺基 - 4 - 18F - 氟苯甲酸酯（18F - SFB）偶联进行18F标记。在PC - 3人前列腺癌细胞中测试了FB - [Lys3]BBN和FB - Aca - BBN(7 - 14)的受体结合亲和力。还评估了两种放射性示踪剂的内化和外排。通过生物分布和动态微型PET成像研究，在携带皮下PC - 3肿瘤的雄性无胸腺裸鼠中检查了两种放射性示踪剂的肿瘤靶向效能和体内动力学。还测试了18F - FB - [Lys3]BBN用于原位PC - 3肿瘤的描绘。在注射后1小时，在小鼠血液、尿液、肝脏、肾脏和肿瘤匀浆中测定18F - FB - [Lys3]BBN的代谢稳定性。
两种示踪剂经衰变校正后的典型放射化学产率约为30% - 40%，从18F - 开始的总反应时间为150±20分钟。18F - FB - [Lys3]BBN在血液和PC - 3肿瘤中具有中等稳定性，而在肝脏、肾脏和尿液中迅速降解。两种放射性示踪剂均表现出快速的血液清除。18F - FB - [Lys3]BBN主要经肾脏排泄。18F - FB - Aca - BBN(7 - 14)表现出肝胆和肾脏清除。动态微型PET成像研究表明，在所有检查时间点，PC - 3肿瘤对18F - FB - [Lys3]BBN的摄取均远高于18F - FB - Aca - BBN(7 - 14)（P < 0.01）。在存在[Tyr4]BBN的情况下，肿瘤摄取有效阻断证明了18F - FB - [Lys3]BBN在体内的受体特异性。在相同条件下使用18F - FB - Aca - BBN(7 - 14)作为放射性示踪剂时，在PC - 3肿瘤中未发现明显阻断。在给予示踪剂后的早期时间点，18F - FB - [Lys3]BBN也能够使原位PC - 3肿瘤显影，此时膀胱活动最小，不会干扰受体介导的肿瘤摄取。
本研究表明18F - FB - [Lys3]BBN和PET适用于体内检测GRPR阳性前列腺癌。
