A triazacyclononane-based bifunctional phosphinate ligand for the preparation of multimeric68GA tracers for positron emission tomography

Article abstract of DOI:10.1002/chem.200903281

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 ⁶⁸Ga³⁺ 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. ⁶⁸Ga 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 TiO₂based ⁶⁸Ge/⁶⁸Ga generator (typically consisting of 0.1M HCl) can be directly used for labeling purposes. The rate of ⁶⁸Ga activity incorporation at pH 3.3 and 20°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.