A Triazacyclononane-Based Bifunctional Phosphinate Ligand for the Preparation of Multimeric 68Ga Tracers for Positron Emission Tomography

For application in positron emission tomography (PET). PrP9, a N,N',N ''-trisubstituted triazacyclononane with methyl(2-carboxyethyl)phosphinic acid pendant arms, was developed as Ga-68(3+) complexing agent. The synthesis is short and inexpensive. Ga-III and Fe-III complexes of PrP9 were characterized by single-crystal X-ray diffraction. Stepwise protonation constants and thermodynamic stabilities of metal complexes were determined by potentiometry. The Ga-III complex possesses a high thermodynamic stability (log K-[GaL]=26.24) and a high degree of kinetic inertness. Ga-68 labeling of PrP9 is possible at ambient temperature and in a wide pH range, also at pH values as low as 1. This means that for the first time, the neat eluate of a TiO2-based Ge-68/Ga-68 generator (typically consisting of 0.1m HCl) can be directly used for labeling purposes. The rate of Ga-68 activity incorporation at pH 3.3 and 20 degrees C is higher than for the established chelators DOTA and NOTA. Tris-amides of PrP9 with amino acid esters were synthesized to act as models for multimeric peptide conjugates. These conjugates exhibit radiolabeling properties similar to those of unsubstituted PrP9.