(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.
Liu
Zhaofei
Z
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.
Niu
Gang
G
Wang
Fan
F
Chen
Xiaoyuan
X
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