Radiofluorination of a Pre-formed Gallium(III) Aza-macrocyclic Complex: Towards Next-Generation Positron Emission Tomography (PET) Imaging Agents

As part of a study to investigate the factors influencing the development of new, more effective metal-complex-based positron emission tomography (PET) imaging agents, the distorted octahedral complex, [GaCl(L)]⋅2 H2O has been prepared by reaction of 1-benzyl-1,4,7-triazacyclononane-4,7-dicarboxylic acid hydrochloride (H2L⋅HCl) with Ga(NO3)3⋅9 H2O, which is a convenient source of Ga(III) for reactions in water. Spectroscopic and crystallographic data for [GaCl(L)]⋅2 H2O are described, together with the crystal structure of [GaCl(L)]⋅MeCN. Fluorination of this complex by Cl(-)/F(-) exchange was achieved in high yield by treatment with KF in water at room temperature over 90 minutes, although the reaction was complete in approximately 30 minutes if heated to 80 °C, giving [GaF(L)]⋅2 H2O in good yield. The same complex was obtained by hydrothermal synthesis from GaF3⋅3 H2O and Li2L, and has been characterised by single-crystal X-ray analysis, IR, (1)H and (19)F{(1)H} NMR spectroscopy and ESI(+) MS. Radiofluorination of the pre-formed [GaCl(L)]⋅2 H2O has been demonstrated on a 210 nanomolar scale in aqueous NaOAc at pH 4 by using carrier-free (18)F(-), leading to 60-70% (18)F-incorporation after heating to 80 °C for 30 minutes. The resulting radioproduct was purified easily by using a solid-phase extraction (SPE) cartridge, leading to 98-99% radiochemical purity. The [Ga(18)F(L)] is stable for at least 90 minutes in 10% EtOH/NaOAc solution at pH 6, but defluorinates over this time scale at pH of approximately 7.5 in phosphate buffered saline (PBS) or human serum albumin (HSA). The subtle role of the Group 13 metal ion and co-ligand donor set in influencing the pH dependence of this system is discussed in the context of developing potential new imaging agents for PET.