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 ⁶⁸Ga 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 N¹–CH₃ group of THP^Me with O (tris(6-methyl-3-hydroxypyran-4-one, THPO) and N¹–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 ⁶⁸Ga 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 ⁶⁸Ga acetate. The ⁶⁷Ga radiolabelled complex was stable in serum for more than 7 days. [⁶⁸Ga(THP^H)] displayed a log P value of −2.40 ± 0.02, less negative than the log P = −3.33 ± 0.02 measured for [⁶⁸Ga(THP^Me)], potentially due to an increase in intramolecular hydrogen bonding attributable to the N¹–H pyridinone units. Spectrophotometric determination of the Ga³⁺/Fe³⁺ complex formation constants for both THP^Me and THP^H revealed their preference for binding Ga³⁺ over Fe³⁺, which enabled selective labelling with ⁶⁸Ga³⁺ in the presence of a large excess of Fe³⁺ in both cases. Compared to THP^Me, THP^H showed significantly reduced affinity for Fe³⁺, increased affinity for Ga³⁺ 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.