Synthesis, Characterization, and Computational Studies on Gallium(III) and Iron(III) Complexes with a Pentadentate Macrocyclic -Phosphinate Chelator and Their Investigation As Molecular Scaffolds for F Binding.

With the aim of obtaining improved molecular scaffolds for F binding to use in PET imaging, gallium(III) and iron(III) complexes with a macrocyclic -phosphinate chelator have been synthesized and their properties, including their fluoride binding ability, investigated. Reaction of Bn-tacn (1-benzyl-1,4,7-triazacyclononane) with paraformaldehyde and PhP(OR) (R = Me or Et) in refluxing THF, followed by acid hydrolysis, yields the macrocyclic (phosphinic acid) derivative, H(Bn-NODP) (1-benzyl-4,7-phenylphosphinic acid-1,4,7-triazacyclononane), which is isolated as its protonated form, H(Bn-NODP)·2HCl·4HO, at low pH (HCl), its disodium salt, Na(Bn-NODP)·5HO at pH 12 (NaOH), or the neutral H(Bn-NODP) under mildly basic conditions (EtN). A crystal structure of H(Bn-NODP)·2HCl·HO confirmed the ligand's identity. The mononuclear [GaCl(Bn-NODP)] complex was prepared by treatment of either the HCl or sodium salt with Ga(NO)·9HO or GaCl, while treatment of H(Bn-NODP)·2HCl·4HO with FeCl in aqueous HCl gives [FeCl(Bn-NODP)]. The addition of 1 mol. equiv of aqueous KF to these chloro complexes readily forms the [MF(Bn-NODP)] analogues. Spectroscopic analysis on these complexes confirms pentadentate coordination of the doubly deprotonated (-phosphinate) macrocycle via its NO donor set, with the halide ligand completing a distorted octahedral geometry; this is further confirmed through a crystal structure analysis on [GaF(Bn-NODP)]·4HO. The complex adopts the geometric isomer in which the phosphinate arms are coordinated unsymmetrically (isomer 1) and with the stereochemistry of the three N atoms of the tacn ring in the configuration, denoted (N) and the phosphinate groups in the stereochemistry, denoted (P) (isomer 1/), together with its (N) (P) enantiomer. The greater thermodynamic stability of isomer 1/ over the other possible isomers is also indicated by density functional theory (DFT) calculations. Radiofluorination experiments on the [MCl(Bn-NODP)] complexes in partially aqueous MeCN/NaOAc (Ga) or EtOH (Ga or Fe; i.e. without buffer) with F target water at 80 °C/10 min lead to high radiochemical incorporation (radiochemical yields 60-80% at 1 mg/mL, or ∼1.5 μM, concentration of the precursor). While the [FeF(n-NODP)] is unstable (loss of F) in both HO/EtOH and PBS/EtOH (PBS = phosphate buffered saline), the [GaF(Bn-NODP)] radioproduct shows excellent stability, RCP = 99% at = 4 h (RCP = radiochemical purity) when formulated in 90%:10% HO/EtOH and . 95% RCP over 4 h when formulated in 90%:10% PBS/EtOH. This indicates that the new "Ga(Bn-NODP)" moiety is a considerably superior fluoride binding scaffold than the previously reported [GaF(Bn-NODA)] (Bn-NODA = 1-benzyl-4,7-dicarboxylate-1,4,7-triazacyclononane), which undergoes rapid and complete hydrolysis in PBS/EtOH (refer to , , 4688-4694).