microPET and autoradiographic imaging of GRP receptor expression with 64Cu-DOTA-[Lys3]bombesin in human prostate adenocarcinoma xenografts.
Overexpression of gastrin-releasing peptide (GRP) receptor (GRPR) in both androgen-dependent (AD) and androgen-independent (AI) human neoplastic prostate tissues provides an attractive target for prostate cancer imaging and therapy. The goal of this study was to develop (64)Cu-radiolabeled GRP analogs for PET imaging of GRPR expression in prostate cancer xenografted mice.


METHODS
[Lys(3)]bombesin ([Lys(3)]BBN) was conjugated with 1,4,7,10-tetraazadodecane-N,N',N",N"'-tetraacetic acid (DOTA) and labeled with the positron-emitting isotope (64)Cu (half-life = 12.8 h, 19% beta(+)). Receptor binding of DOTA-[Lys(3)]BBN and internalization of (64)Cu-DOTA-[Lys(3)]BBN by PC-3 prostate cancer cells were measured. Tissue biodistribution, microPET, and whole-body autoradiographic imaging of the radiotracer were also investigated in PC-3 (AI)/CRW22 (AD) prostate cancer tumor models.


RESULTS
A competitive receptor- binding assay using (125)I-[Tyr(4)]BBN against PC-3 cells yielded a 50% inhibitory concentration value of 2.2 +/- 0.5 nmol/L for DOTA-[Lys(3)]BBN. Incubation of cells with the (64)Cu-labeled radiotracer showed temperature- and time-dependent internalization. At 37 degrees C, >60% of the tracer was internalized within the first 15 min and uptake remained constant for 2 h. Radiotracer uptake was higher in AI PC-3 tumor (5.62 +/- 0.08 %ID/g at 30 min after injection, where %ID/g is the percentage of injected dose per gram) than in AD CWR22 tumor (1.75 +/- 0.05 %ID/g at 30 min after injection). Significant accumulation of the activity in GRPR-positive pancreas was also observed (10.4 +/- 0.15 %ID/g at 30 min after injection). Coinjection of a blocking dose of [Lys(3)]BBN inhibited the activity accumulation in PC-3 tumor and pancreas but not in CWR22 tumor. microPET and autoradiographic imaging of (64)Cu-DOTA-[Lys(3)]BBN in athymic nude mice bearing subcutaneous PC-3 and CWR22 tumors showed strong tumor-to-background contrast.


CONCLUSIONS
This study demonstrates that PET imaging of (64)Cu-DOTA-[Lys(3)]BBN is able to detect GRPR-positive prostate cancer.
PET Imaging Science Center, University of Southern California Keck School of Medicine, Los Angeles 90033, USA.
Xiaoyuan
X
Chen
Ryan
R
Park
Yingping
Y
Hou
Michel
M
Tohme
Antranik H
AH
Shahinian
James R
JR
Bading
Peter S
PS
Conti
D000230:Adenocarcinoma / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001345:Autoradiography; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001839:Bombesin / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008819:Mice, Nude; D009928:Organ Specificity; D009942:Organometallic Compounds / Q000493:pharmacokinetics*; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism* / Q000473:pathology; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D018004:Receptors, Bombesin / Q000378:metabolism*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed / Q000295:instrumentation / Q000379:methods*; D014183:Transplantation, Heterologous
D014408:Biomarkers, Tumor; C490526:Cu-DOTA-(Lys3)bombesin; D009942:Organometallic Compounds; D019275:Radiopharmaceuticals; D018004:Receptors, Bombesin; D001839:Bombesin