A range of macrocyclic and acyclic chelators have been reacted with the PET isotope, gallium-68, and their radiolabelling efficiencies have been compared. Structural data for complexes of HBED with Ga³⁺ are reported.

A tris(hydroxypyridinone) chelator coordinates the PET imaging isotope, ⁸⁹Zr⁴⁺, rapidly and quantitatively under ambient conditions, but a ⁸⁹Zr-labelled tris(hydroxypyridinone)-immunoconjugate is not stable to in vivo demetallation.

Derivatives of 3,4-hydroxypyridinones have been extensively studied for in vivo Fe³⁺ sequestration. Deferiprone, a 1,2-dimethyl-3,4-hydroxypyridinone, is now routinely used for clinical treatment of iron overload disease. Hexadentate tris(3,4-hydroxypyridinone) ligands (THP) complex Fe³⁺ at very low iron concentrations, and their high affinities for oxophilic trivalent metal ions have led to their development for new applications as bifunctional chelators for the positron emitting radiometal, ⁶⁸Ga³⁺, which is clinically used for molecular imaging in positron emission tomography (PET). THP-peptide bioconjugates rapidly and quantitatively complex ⁶⁸Ga³⁺ at ambient temperature, neutral pH and micromolar concentrations of ligand, making them amenable to kit-based radiosynthesis of ⁶⁸Ga PET radiopharmaceuticals. ⁶⁸Ga-labelled THP-peptides accumulate at target tissue in vivo, and are excreted largely via a renal pathway, providing high quality PET images.

Two new bifunctional tris(hydroxypyridinone) (THP) chelators designed specifically for rapid labeling with ⁶⁸Ga have been synthesized, each with pendant isothiocyanate groups and three 1,6-dimethyl-3-hydroxypyridin-4-one groups. Both compounds have been conjugated with the primary amine group of a cyclic integrin targeting peptide, RGD. Each conjugate can be radiolabeled and formulated by treatment with generator-produced ⁶⁸Ga³⁺ in over 95% radiochemical yield under ambient conditions in less than 5 min, with specific activities of 60–80 MBq nmol^–1. Competitive binding assays and in vivo biodistribution in mice bearing U87MG tumors demonstrate that the new ⁶⁸Ga³⁺-labeled THP peptide conjugates retain affinity for the α_vβ₃ integrin receptor, clear within 1–2 h from circulation, and undergo receptor-mediated tumor uptake in vivo. We conclude that bifunctional THP chelators can be used for simple, efficient labeling of ⁶⁸Ga biomolecules under mild conditions suitable for peptides and proteins.