Gallium-68 (⁶⁸Ga) has a decay profile suitable for PET imaging (t½=68 min, 90% β⁺ yield) and is from a long-lived ⁶⁸Ge/⁶⁸Ga generator. Emerging novel chelators allow the precursor chelator-bioconjugates to be labelled with different radiometals, thus paving the way to theranostic applications.
The tris(hydroxypyridinone) (H₃THP¹) chelator (Figure 1a) efficiently binds ⁶⁸Ga³⁺ under mild conditions [1] its radiolabelled peptide derivatives target tumours in vivo [2]. However, retention of such derivatives in non-target tissue suggests that modification of the chelator will improve clearance from non-target organs. Herein we report the synthesis of a second generation tris(hydroxypyridinone) chelator, H₃THP², with significantly improved aqueous solubility, where the N-methyl group in the hydroxypyridinone unit has been replaced by hydrogen. Like H₃THP¹, H₃THP² coordinates ⁶⁸Ga³⁺ under mild conditions and at low ligand concentration, achieving high (quantitative) radiochemical yield and specific activity. Furthermore, competition studies demonstrate that [⁶⁸Ga(THP²)] forms preferentially to [⁶⁸Ga(THP¹)]. Preliminary preclinical experiments proved that [⁶⁸Ga(THP²)] is stable in vivo and quickly clears from the blood renally. Intriguingly, H₃THP² is also able to clear ⁶⁸Ga from the blood pool of a mouse preinjected with acetate buffered ⁶⁸Ga³⁺, forming [⁶⁸Ga(THP²)] in vivo.

Figure 1 a) Chemical structures of H₃THP ligands. b) New synthetic route for the hydroxypyridinone precursor 3. Compound 1 was synthesized in 4 steps from Kojic acid following literature procedures¹.

1) Berry D.J et al., Chemical Communications, 2011, 47, 7068.

2) Ma, M.T, Imberti, C. et al., Bioconjugate Chemistry, 2016, 27 (2), 309.