Synthesis, Characterization, and Computational Studies on Gallium(III) and Iron(III) Complexes with a Pentadentate Macrocyclic bis -Phosphinate Chelator and Their Investigation As Molecular Scaffolds for 18 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·4H O, at low pH (HCl ), its disodium salt, Na (Bn-NODP)·5H O at pH 12 (NaOH ), or the neutral H (Bn-NODP) under mildly basic conditions (Et N). A crystal structure of H (Bn-NODP)·2HCl·H O 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 ) ·9H O or GaCl , while treatment of H (Bn-NODP)·2HCl·4H O 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 N O donor set, with the halide ligand completing a distorted octahedral geometry; this is further confirmed through a crystal structure analysis on [GaF(Bn-NODP)]·4H O. 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 [Fe F(n-NODP)] is unstable (loss of F ) in both H O/EtOH and PBS/EtOH (PBS = phosphate buffered saline), the [Ga F(Bn-NODP)] radioproduct shows excellent stability, RCP = 99% at = 4 h (RCP = radiochemical purity) when formulated in 90%:10% H O/Et