(68)Ga-labeled NOTA-RGD-BBN peptide for dual integrin and GRPR-targeted tumor imaging.
OBJECTIVE
Radiolabeled Arg-Gly-Asp (RGD) and bombesin (BBN) peptide analogs have been extensively investigated for the imaging of tumor integrin alpha(v)beta(3) and gastrin-releasing peptide receptor (GRPR) expression, respectively. Recently, we designed and synthesized a RGD-BBN heterodimeric peptide from c(RGDyK) and BBN(7-14) through a glutamate linker. The goal of this study was to investigate the dual receptor-targeting property and tumor diagnostic value of RGD-BBN heterodimeric peptide labeled with generator-eluted (68)Ga (t(1/2) 68 min, beta(+) 89% and EC 11%), (68)Ga-NOTA-RGD-BBN.


METHODS
RGD-BBN heterodimer was conjugated with 1,4,7-triazacyclononanetriacetic acid (NOTA) and labeled with (68)Ga. The dual receptor binding affinity was investigated by a radioligand competition binding assay. The in vitro and in vivo dual receptor targeting of (68)Ga-NOTA-RGD-BBN was evaluated and compared with that of (68)Ga-NOTA-RGD and (68)Ga-NOTA-BBN.


RESULTS
NOTA-RGD-BBN had integrin alpha(v)beta(3) and GRPR binding affinities comparable to those of the monomeric RGD and BBN, respectively. The dual receptor targeting property of (68)Ga-NOTA-RGD-BBN was validated by blocking studies in a PC-3 tumor model. (68)Ga-NOTA-RGD-BBN showed higher tumor uptake than (68)Ga-NOTA-RGD and (68)Ga-NOTA-BBN. (68)Ga-NOTA-RGD-BBN can also image tumors with either integrin or GRPR expression.


CONCLUSIONS
(68)Ga-NOTA-RGD-BBN exhibited dual receptor targeting properties both in vitro and in vivo. The favorable characterizations of (68)Ga-NOTA-RGD-BBN such as convenient synthesis, high specific activity, and high tumor uptake, warrant its further investigation for clinical cancer imaging.
The Molecular Imaging Program at Stanford (MIPS), Department of Radiology and Bio-X Program, Stanford University School of Medicine, 1201 Welch Rd, P095, Stanford, CA 94305-5484, USA.
Zhaofei
Z
Liu
Gang
G
Niu
Fan
F
Wang
Xiaoyuan
X
Chen
D000818:Animals; D001839:Bombesin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D005260:Female; D005710:Gallium Radioisotopes; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry / Q000493:pharmacokinetics*; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000819:agonists / Q000378:metabolism*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009842:Oligopeptides / Q000737:chemistry / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000737:chemistry / Q000493:pharmacokinetics*; D018004:Receptors, Bombesin / Q000819:agonists / Q000378:metabolism*
D005710:Gallium Radioisotopes; D006573:Heterocyclic Compounds, 1-Ring; D039302:Integrin alphaVbeta3; D009842:Oligopeptides; D019275:Radiopharmaceuticals; D018004:Receptors, Bombesin; C047981:arginyl-glycyl-aspartic acid; D001839:Bombesin