New Tris(hydroxypyridinone) Bifunctional Chelators Containing Isothiocyanate Groups Provide a Versatile Platform for Rapid One-Step Labeling and PET Imaging with ⁶⁸Ga³⁺

Abstract

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 αvβ3 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.

Investigation of the complexation of natZr(iv) and 89Zr(iv) by hydroxypyridinones for the development of chelators for PET imaging applications

“…5 In the field of nuclear medicine, HOPOs have also been studied as ligands of Ga(III), whose radioisotopes 67 Ga and 68 Ga can be used for nuclear imaging. 6–8 …”

“…The development of HOPO based chelators for nuclear imaging application is not new and several examples of chelators for 67 Ga or 68 Ga complexation have been reported over the recent years. 7,8,31 In line with these reported applications, bifunctional HOPO based chelators for 89 Zr complexation have recently been developed and studied in vivo with varying degrees of success. 30,32,33 The most stable to date, p -SCN-Bn-HOPO which is based on the 1,2-HOPO subunit, released a significantly lower fraction of the 89 Zr activity to the bone in comparison with the same antibody radiolabeled using DFB-SCN.…”

Molecular Imaging with 68Ga Radio-Nanomaterials: Shedding Light on Nanoparticles

“…Ma and coworkers used two THP conjugates, combined with the tumor-targeting peptide Arginine-Glycine-Aspartic (RGD), in murine models to detect U87MG tumors. They managed to radiolabel these conjugates with over 95% radiochemical yield under ambient conditions in less than 5 min, achieving activities ranging from 60 to 80 MBq·nmol −1 [65]. 68 Ga include a family of cyclic ligands based on heterocyclic N-dodecane or N-nonane moieties.…”

Re-assessing gallium-67 as a therapeutic radionuclide

“…In recent years the development of peptides and proteins labeled with 68 Ga, arising from the growing popularity of the 68 Ga generator for positron emission tomography applications, has led to a new generation of effective bifunctional chelators for gallium [15][16][17][18][19][20][21][22][23][24][25]. For example, the trishydroxypyridinone chelator allows radiolabelling of molecular targeting agents with gallium using fast and simple onestep procedures [15,20].…”

“…For example, the trishydroxypyridinone chelator allows radiolabelling of molecular targeting agents with gallium using fast and simple onestep procedures [15,20]. The resulting enhanced versatility and range of potentially useful targeting agents now presents an opportunity to reconsider 67 Ga as a targeted therapeutic radionuclide.…”