Woodward, Madeleine Serena (2023) Developing new metal-based complexes for 18F-based positron emission tomography (PET) applications. University of Southampton, Doctoral Thesis, 203pp.
Abstract
The coordination chemistry of Group 14 fluoride complexes towards hard N– and O-donor ligands was developed. The pseudo-octahedral complexes [SnF4(L)2] have been prepared and further characterisation detail has been acquired than present in the literature. The reactions of [SnF4(L)2] with trimethylsilyl trifluoromethanesulfonate (TMSOTf) and one equivalent of appropriate ligand gave the novel, octahedral cationic complexes [SnF3(L)3][OTf] (L = dmf, dmso, pyridine N-oxide (pyNO), pyridine (py) and OPPh3). Further tests on removing fluoride in the presences of OPPh3 showed that it was possible to prepare and characterise the first reported example of a phosphine oxide dicationic tin(IV) fluoride phosphine oxide complex, [SnF2(OPPh3)4][OTf]2.
Similarly, the novel complexes [GeF4(L)2] (L = dmso, dmf and pyNO) and known complexes [GeF4(L’)2] (L’ = py, OPPh3, OPMe3 and OAsPh3) were prepared from reactions of [GeF4(MeCN)2] with the appropriate ligand. The reactions of [GeF4(L)2] with TMSOTf and one equivalent of appropriate ligand gave the novel, octahedral cationic complexes [GeF3(L)3][OTf] (L = dmso, dmf, pyNO, py, OPPh3, OPMe3 and OAsPh3). All of the complexes have been characterised by microanalysis, IR, 1H, 31p{1H}, 19F{1H} and spectroscopy, where appropriate.
Reactions of [MF4(MeCN)2] (M = Sn, Ge) with tetradentate macrocyclic ligands, 1,4,8,11-tetramethyltetraazacyclotetradecane (Me4-cyclam) and 1,4,7,10-tetramethyltetraazacyclododecane (Me4-cyclen), yields the rare Group 14 difluoride dicationic complexes, cis-[MF2(Me4- cyclam)][OTf]2 and [MF2(Me4-cyclen)][OTf]2, the former a mixture of cis and trans isomers. Similar attempts using SiX4 (X = Cl or I) did not produced the dicationic complexes.
A new hydrothermal synthesis route to [GaF3(pyNO)(H2O)2] was developed and the complex was tested to determine whether it could be used as a synthon to access a new route to [GaF3(BnMe2tacn)] in the absence of a highly coordinating solvent or competing anions. An attempt at a [18F]fluoride radiolabelling experiment demonstrated that this route did produce a more radio-stable formulation of [Ga18F19F2(BnMe2tacn)], showing a radiochemical purity (RCP) of >99% after three hours, however repeat experiments were unable to replicate these results.
The automation of the synthesis of [Fe18F19F2(BnMe2tacn)] has been developed and optimised using the GE HealthCare’s FAST lab, a commercially available synthesis module. Variation of parameters including pH, eluent concentration, temperature and organic: aqueous solvent ratio were undertaken. The RCP of the finalised reaction at a precursor concentration of 2.68 μM was >99% at t=0. High activity work (up to 30 GBq) was undertaken at Addenbrooke’s Hospital subsequently and several radiostabilisers were tested for their suitability; a reaction starting at 26.1 GBq, the RCP of [Fe18F19F2(BnMe2tacn)] was shown to have a radio-stability of 86% at t = 3 h in the presence of nicotinamide (5 mg/mL). This work showed that it is feasible to transfer these systems over to automation, as a proof of concept, and will allow more work on similar Fe(III) systems with bioconjugates by starting with this developed protocol.
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