The prototype tris(1,6-dimethyl-3-hydroxypyridin-4-one) chelator for gallium-68, THP Me , has shown great promise for rapid and efficient kit-based 68 Ga labelling of PET radiopharmaceuticals. Peptide derivatives of THP Me 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 -CH 3 group of THP Me with O (tris(6-methyl-3-hydroxypyran-4-one, THPO) and N 1 -H (tris(6-methyl-3-hydroxypyridin-4-one), THP H ) groups. The effect of these structural modifications on lipophilicity, gallium binding and metal ion selectivity was investigated. THP H was able to bind 68 Ga in extremely mild conditions (5 min, room temperature, pH 6, 1 μM ligand concentration) and, notably, in vivo, when administered to a mouse previously injected with 68 Ga acetate. The 67 Ga radiolabelled complex was stable in serum for more than 7 days. [ 68 Ga(THP H )] displayed a logP value of -2.40 ± 0.02, less negative than the logP = -3.33 ± 0.02 measured for [ 68 Ga(THP Me )], potentially due to an increase in intramolecular hydrogen bonding attributable to the N 1 -H pyridinone units. Spectrophotometric determination of the Ga 3+ /Fe 3+ complex formation constants for both THP Me and THP H revealed their preference for binding Ga 3+ over Fe 3+ , which enabled selective labelling with 68 Ga 3+ in the presence of a large excess of Fe 3+ in both cases. Compared to THP Me , THP H showed significantly reduced affinity for Fe 3+ , increased affinity for Ga 3+ and improved radiolabelling efficiency. THPO was inferior to both THP H and THP Me 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.