(68)Ga-labeled multimeric RGD peptides for microPET imaging of integrin alpha(v)beta (3) expression.
OBJECTIVE
We and others have reported that (18)F- and (64)Cu-labeled arginine-glycine-aspartate (RGD) peptides allow positron emission tomography (PET) quantification of integrin alpha(v)beta(3) expression in vivo. However, clinical translation of these radiotracers is partially hindered by the necessity of cyclotron facility to produce the PET isotopes. Generator-based PET isotope (68)Ga, with a half-life of 68 min and 89% positron emission, deserves special attention because of its independence of an onsite cyclotron. The goal of this study was to investigate the feasibility of (68)Ga-labeled RGD peptides for tumor imaging.


METHODS
Three cyclic RGD peptides, c(RGDyK) (RGD1), E[c(RGDyK)](2) (RGD2), and E{E[c(RGDyK)](2)}(2) (RGD4), were conjugated with macrocyclic chelator 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) and labeled with (68)Ga. Integrin affinity and specificity of the peptide conjugates were assessed by cell-based receptor binding assay, and the tumor targeting efficacy of (68)Ga-labeled RGD peptides was evaluated in a subcutaneous U87MG glioblastoma xenograft model.


RESULTS
U87MG cell-based receptor binding assay using (125)I-echistatin as radioligand showed that integrin affinity followed the order of NOTA-RGD4 > NOTA-RGD2 > NOTA-RGD1. All three NOTA conjugates allowed nearly quantitative (68)Ga-labeling within 10 min (12-17 MBq/nmol). Quantitative microPET imaging studies showed that (68)Ga-NOTA-RGD4 had the highest tumor uptake but also prominent activity accumulation in the kidneys. (68)Ga-NOTA-RGD2 had higher tumor uptake (e.g., 2.8 +/- 0.1%ID/g at 1 h postinjection) and similar pharmacokinetics (4.4 +/- 0.4 tumor/muscle ratio, 2.0 +/- 0.1 tumor/liver ratio, and 1.1 +/- 0.1 tumor/kidney ratio) compared with (68)Ga-NOTA-RGD1.


CONCLUSIONS
The dimeric RGD peptide tracer (68)Ga-NOTA-RGD2 with good tumor uptake and favorable pharmacokinetics warrants further investigation for potential clinical translation to image integrin alpha(v)beta(3).
Li
Zi-Bo
ZB
Department of Radiology, Stanford University School of Medicine, Stanford, CA 94305-5484, USA.
Chen
Kai
K
Chen
Xiaoyuan
X
D000818:Animals; D045744:Cell Line, Tumor; D019281:Dimerization; D005260:Female; D005710:Gallium Radioisotopes / Q000493:pharmacokinetics; D005909:Glioblastoma / Q000000981:diagnostic imaging* / Q000378:metabolism*; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D007553:Isotope Labeling; D008657:Metabolic Clearance Rate; D051379:Mice; D008819:Mice, Nude; D009842:Oligopeptides / Q000737:chemistry / Q000493:pharmacokinetics*; D009928:Organ Specificity; D049268:Positron-Emission Tomography / Q000379:methods* / Q000662:veterinary*; D019275:Radiopharmaceuticals / Q000737:chemistry / Q000493:pharmacokinetics; D014018:Tissue Distribution
D005710:Gallium Radioisotopes; D039302:Integrin alphaVbeta3; D009842:Oligopeptides; D019275:Radiopharmaceuticals; C047981:arginyl-glycyl-aspartic acid