Comparative in vitro and in vivo evaluation of two 64Cu-labeled bombesin analogs in a mouse model of human prostate adenocarcinoma

Yang, Yi-Shan; Zhang, Xianzhong; Xiong, Zhengming; Chen, Xiaoyuan

doi:10.1016/j.nucmedbio.2005.12.011

« Previous Next »Nuclear Medicine and Biology
Volume 33, Issue 3 , Pages 371-380, April 2006

Comparative in vitro and in vivo evaluation of two ⁶⁴Cu-labeled bombesin analogs in a mouse model of human prostate adenocarcinoma

Department of Radiology and Bio-X Program, The Molecular Imaging Program at Stanford (MIPS), Stanford University School of Medicine, Stanford, CA 94305-5484, USA

Received 9 October 2005; received in revised form 30 November 2005; accepted 4 December 2005. published online 13 March 2006.

Abstract

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±0.1×10⁶ 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.