Tuning the properties of tris(hydroxypyridinone) ligands: efficient Ga chelators for PET imaging.

The prototype tris(1,6-dimethyl-3-hydroxypyridin-4-one) chelator for gallium-68, THPMe, has shown great promise for rapid and efficient kit-based Ga-68 labelling of PET radiopharmaceuticals. Peptide derivatives of THPMe have been used to image expression of their target receptors in vivo in preclinical and clinical studies. Herein we describe new synthetic routes to the THP platform including replacing the 1,6-dimethyl-3-hydroxypyridin-4-one N-1-CH3 group of THPMe with O (tris(6-methyl-3-hydroxypyran-4-one, THPO) and N-1-H (tris(6-methyl-3-hydroxypyridin-4-one), THPH) groups. The effect of these structural modifications on lipophilicity, gallium binding and metal ion selectivity was investigated. THPH was able to bind Ga-68 in extremely mild conditions (5 min, room temperature, pH 6, 1 M ligand concentration) and, notably, in vivo, when administered to a mouse previously injected with Ga-68 acetate. The Ga-67 radiolabelled complex was stable in serum for more than 7 days. [Ga-68(THPH)] displayed a logP value of -2.40 +/- 0.02, less negative than the logP = -3.33 +/- 0.02 measured for [Ga-68(THPMe)], potentially due to an increase in intramolecular hydrogen bonding attributable to the N-1-H pyridinone units. Spectrophotometric determination of the Ga3+/Fe3+ complex formation constants for both THPMe and THPH revealed their preference for binding Ga3+ over Fe3+, which enabled selective labelling with Ga-68(3+) in the presence of a large excess of Fe3+ in both cases. Compared to THPMe, THPH showed significantly reduced affinity for Fe3+, increased affinity for Ga3+ and improved radiolabelling efficiency. THPO was inferior to both THPH and THPMe in terms of labelling efficiency, but its benzylated precursor Bn-THPO (tris(6-methyl-3-benzyloxypyran-4-one)) provides a potential platform for the synthesis of a library of THP compounds with tunable chemical properties and metal preferences.