Transition metal and Group 13 triazamacrocyclic complexes: Coordination chemistry and applications in 18F PET imaging

O'Callaghan, Charley Nicole Susan (2025) Transition metal and Group 13 triazamacrocyclic complexes: Coordination chemistry and applications in 18F PET imaging. University of Southampton, Doctoral Thesis, 265pp.

Record type: Thesis (Doctoral)

Abstract

Three novel triazacyclononane ligands bearing phenylacetamide or isopropylacrylamide pendant arms (L1, L2, L3) are reported with their full spectroscopic data, alongside known triazacyclononane ligands with carboxylate (H2-Bn-NODA) and phosphinate ester (NOTP-OMe) functionality. New automated purification techniques have also been developed.

The coordination chemistry of the tris(amide) ligands L1 and L2 has been established with the divalent first-row transition metals, Co2+, Ni2+, Cu2+ and Zn2+, and the complexes characterised
using IR, 1H and 13C{1H} NMR (Zn only) and UV-Vis spectroscopy, ESI+ MS, microanalysis and SCXRD. Molecular structures of Co, Ni and Cu complexes of L1 and L2 are reported, with the ligands adopting hexadentate coordination with an N3O3 or N4O2 donor set. Preliminary methods towards Ni, Cu and Zn complexes of NOTP-OMe are discussed.

Routes towards MF3 complexes of L1, L2 and L3 using a molecular MF3 precursor, FeF3.3H2O or [MF3(dmso)(OH2)2] are reported. The products are characterised using IR, 1H, 13C{1H} NMR, 19F{1H} NMR spectroscopy, microanalysis, ESI+ MS and SCXRD. The coordinative properties of the ligands with MF3 are determined via the molecular structures for [GaF3(L1)], [InF3(L2)], [GaF3(L3)] and [FeF3(L3)]. Any supramolecular features or extended hydrogen-bonded networks are discussed. Potential candidates for 18F-radiolabelling experiments are identified based on the characterisation data, with consideration towards metal-fluoride bond strength, hydrogen-bonded interactions involving fluoride ligands and the stability of the complexes in solution.

New HPLC methodologies were developed for analysis of the radiochemical reactions involving [GaF3(L1)] and [GaF3(L3)]. [GaF3(L1)] shows 18F incorporation under various conditions, with a maximum RCY of 20% achieved after 10 min at 80 °C (3 μmol mL-1). The crude product was purified using an SPE cartridge and formulated in 10:90 EtOH/H2O and EtOH/PBS. The starting
RCP’s were 68% and 64%, respectively, with 7% and 5% degradation observed after 2 h.
Meanwhile, [GaF3(L3)] does not undergo radiofluorination under any conditions.

Alternative routes towards Group 13 fluoride complexes have been explored, using the Lewis acidic M3+ cations. The stability of amide-pendant arms is investigated via coordination of L1 to Fe3+, Ga3+ and In3+. Additionally, various pathways involving L1, H3-NOTA, H2-Bn-NODA and H2-Bn-NODP have been explored, via addition of K19F to six- or seven-coordinate complexes thereof.
From this, the coordination chemistry of the known [In(NOTA)] complex has been further
examined using electron diffraction analysis, showing a highly unusual tetrameric species. In developing methods towards new Al–F complexes, the chemistry of the ‘Al-19F2+’ reaction has been probed at a preparative scale, with the previously unobserved [Al(Bn-NODA)(OAc)] species
identified as a reaction product in addition to [AlF(Bn-NODA)].