[68Ga]NODAGA-RGD for imaging αvβ3 integrin expression

Purpose A molecular target involved in the angiogenic process is the alpha(v)beta(3) integrin. It has been demonstrated in preclinical as well as in clinical studies that radiolabelled RGD peptides and positron emission tomography (PET) allow noninvasive monitoring of alpha(v)beta(3) expression. Here we introduce a Ga-68-labelled NOTA-conjugated RGD peptide ([Ga-68]NODAGA-RGD) and compare its imaging properties with [Ga-68]DOTA-RGD using small animal PET. Methods Synthesis of c(RGDfK(NODAGA)) was based on solid phase peptide synthesis protocols using the Fmoc strategy. The Ga-68 labelling protocol was optimized concerning temperature, peptide concentration and reaction time. For in vitro characterization, partition coefficient, protein binding properties, serum stability, alpha(v)beta(3) binding affinity and cell uptake were determined. To characterize the in vivo properties, biodistribution studies and microPET imaging were carried out. For both in vitro and in vivo evaluation, alpha(v)beta(3)-positive human melanoma M21 and alpha(v)beta(3)-negative M21-L cells were used. Results [Ga-68]NODAGA-RGD can be produced within 5 min at room temperature with high radiochemical yield and purity (> 96%). In vitro evaluation showed high alpha(v)beta(3) binding affinity (IC50=4.7 +/- 1.6 nM) and receptor-specific uptake. The radiotracer was stable in phosphate-buffered saline, pH 7.4, FeCl3 solution, and human serum. Protein-bound activity after 180 min incubation was found to be 12-fold lower than for [Ga-68]DOTA-RGD. Biodistribution data 60 min post-injection confirmed receptor-specific tumour accumulation. The activity concentration of [Ga-68]NODAGA-RGD was lower than [Ga-68]DOTA-RGD in all organs and tissues investigated, leading to an improved tumour to blood ratio ([Ga-68]NODAGA-RGD: 11, [Ga-68]DOTA-RGD: 4). Micro-PET imaging confirmed the improved imaging properties of [Ga-68]NODAGA-RGD compared to [Ga-68]DOTA-RGD. Conclusion The introduced [Ga-68]NODAGA-RGD combines easy accessibility with high stability and good imaging properties making it an interesting alternative to the F-18-labelled RGD peptides currently used for imaging alpha(v)beta(3) expression.