18F-labeled BBN-RGD heterodimer for prostate cancer imaging.
Both bombesin (BBN) analogs and cyclic RGD peptides have been suitably radiolabeled for prostate cancer imaging. However, the limited expression of gastrin-releasing peptide receptor (GRPR) and integrin alpha(v)beta(3) as well as unfavorable in vivo kinetics limited further applications of these imaging agents. We hypothesize that a peptide ligand recognizing both GRPR and integrin will be advantageous because of its dual-receptor-targeting ability.


METHODS
A BBN-RGD heterodimer was synthesized from bombesin(7-14) and c(RGDyK) through a glutamate linker and then labeled with (18)F via the N-succinimidyl-4-(18)F-fluorobenzoate ((18)F-SFB) prosthetic group. The receptor-binding characteristics and tumor-targeting efficacy of (18)F-FB-BBN-RGD were tested in vitro and in vivo.


RESULTS
FB-BBN-RGD had comparable integrin alpha(v)beta(3)-binding affinity with c(RGDyK) and comparable GRPR-binding affinity with BBN(7-14). (18)F-FB-BBN-RGD had significantly higher tumor uptake compared with monomeric RGD and monomeric BBN peptide tracer analogs at all time points examined. The PC-3 tumor uptake of (18)F-FB-BBN-RGD was inhibited only partially in the presence of an excess amount of unlabeled BBN(7-14) or c(RGDyK) but was blocked completely in the presence of both BBN(7-14) and c(RGDyK). Compared with (18)F-FB-BBN and (18)F-FB-RGD, (18)F-FB-BBN-RGD also had improved pharmacokinetics, resulting in a significantly higher imaging quality.


CONCLUSIONS
Dual integrin alpha(v)beta(3) and GRPR recognition showed significantly improved tumor-targeting efficacy and pharmacokinetics compared with (18)F-labeled RGD and BBN analogs. The same heterodimeric ligand design may also be applicable to other receptor system combinations and other imaging modalities.
Li
Zi-Bo
ZB
Molecular Imaging Program at Stanford, Department of Radiology, Biophysics, and Bio-X Program, Stanford University School of Medicine, Stanford, California 94305-5484, USA.
Wu
Zhanhong
Z
Chen
Kai
K
Ryu
Eun Kyoung
EK
Chen
Xiaoyuan
X
D000818:Animals; D001839:Bombesin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D019281:Dimerization; D006801:Humans; D007553:Isotope Labeling; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008819:Mice, Nude; D009842:Oligopeptides / Q000737:chemistry / Q000493:pharmacokinetics*; D009928:Organ Specificity; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism*; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D014018:Tissue Distribution
C528812:(18)F-FB-BBN-RGD; D009842:Oligopeptides; D019275:Radiopharmaceuticals; D001839:Bombesin