A new triazacyclononane-based ligand for trivalent 68Ga tracers of high stability for positron emission tomography

1473 Objectives Gallium-68 is one of the emerging radionuclides in molecular imaging due to its availability from a generator. It forms stable complexes with 1,4,7-triazacyclononane-1,4,7- triacetic acid (NOTA). Since multivalent peptide agents exhibit higher avidity to their targets than their monovalent counterparts, we designed and synthesized a new NOTA based bifunctional ligand, 1,4,7-triazacyclononane-1,4,7-triglutaric acid (NOTGA). 67Ga labeling efficiency and stability of the 67Ga complex were compared with a previously reported ligand, 1,4,7-triazacyclononane-1,4,7-tris[methyl(2-carboxyethyl)phosphinic acid (PrP9). Methods α-Bromo glutaric acid 1-tert-butyl ester 5-benzyl ester was synthesized and reacted with 1,4,7-triazacyclononane. After removing the benzyl groups, phenethylamine (PEA) or cRGDfK peptide was conjugated. PrP9 was also conjugated to PEA. To characterize 67Ga-labeled compounds, non-radioactive Ga complexes were synthesized and characterized. The stability of HPLC purified 67Ga-labeled compounds was estimated in the presence of human apo-transferrin. The biodistribution of 67Ga-NOTGA-RGD3 in mice were determind. Results Both NOTGA-PEA and PrP9-PEA quantitatively provided 67Ga-labeled compounds within 15 min at 100 °C, pH 3 with the ligand concentration of 10 μM. The HPLC retention times of each 67Ga-labeled compound were identical to those of their non-radioactive complexes. However, PrP9 generated two complexes, which is attributable to two enantiomers. 67Ga-NOTGA-PEA remained stable in the presence of human apo-transferrin. 67Ga-NOTGA-RGD3 showed the rapid clearance from blood and the majority of the radioactivity was excreted via kidney. Conclusions NOTGA would constitute a useful ligand for developing 68Ga-labeled trivalent probes of high urinary excretion without impairing the inherent chelating ability of NOTA