18F-labeled bombesin analogs for targeting GRP receptor-expressing prostate cancer.
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.


METHODS
[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.


RESULTS
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.


CONCLUSIONS
This study demonstrates that 18F-FB-[Lys3]BBN and PET are suitable for detecting GRPR-positive prostate cancer in vivo.
Zhang
Xianzhong
X
Molecular Imaging Program at Stanford (MIPS), Department of Radiology and Bio-X Program, Stanford University School of Medicine, Stanford, California 94305-5484, USA.
Cai
Weibo
W
Cao
Feng
F
Schreibmann
Eduard
E
Wu
Yun
Y
Wu
Joseph C
JC
Xing
Lei
L
Chen
Xiaoyuan
X
D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001839:Bombesin / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems / Q000379:methods; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008819:Mice, Nude; D009928:Organ Specificity; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism*; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D018004:Receptors, Bombesin / Q000378:metabolism*; D014018:Tissue Distribution
D014408:Biomarkers, Tumor; D005462:Fluorine Radioisotopes; D019275:Radiopharmaceuticals; D018004:Receptors, Bombesin; D001839:Bombesin