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 18 F binding to use in PET imaging, gallium(III) and iron(III) complexes with a macrocyclic bis -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) 2 (R = Me or Et) in refluxing THF, followed by acid hydrolysis, yields the macrocyclic bis (phosphinic acid) derivative, H 2 (Bn-NODP) (1-benzyl-4,7-phenylphosphinic acid-1,4,7-triazacyclononane), which is isolated as its protonated form, H 2 (Bn-NODP)·2HCl·4H 2 O, at low pH (HCl aq ), its disodium salt, Na 2 (Bn-NODP)·5H 2 O at pH 12 (NaOH aq ), or the neutral H 2 (Bn-NODP) under mildly basic conditions (Et 3 N). A crystal structure of H 2 (Bn-NODP)·2HCl·H 2 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 3 ) 3 ·9H 2 O or GaCl 3 , while treatment of H 2 (Bn-NODP)·2HCl·4H 2 O with FeCl 3 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 ( bis -phosphinate) macrocycle via its N 3 O 2 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 2 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 RRS configuration, denoted (N) RRS, and the phosphinate groups in the RR stereochemistry, denoted (P) RR, (isomer 1/ RR ), together with its (N) SSR (P) SS enantiomer. The greater thermodynamic stability of isomer 1/ RR 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 aq (Ga) or EtOH (Ga or Fe; i.e. without buffer) with 18 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 18 F(n-NODP)] is unstable (loss of 18 F - ) in both H 2 O/EtOH and PBS/EtOH (PBS = phosphate buffered saline), the [Ga 18 F(Bn-NODP)] radioproduct shows excellent stability, RCP = 99% at t = 4 h (RCP = radiochemical purity) when formulated in 90%:10% H 2 O/EtOH and ca . 95% RCP over 4 h when formulated in 90%:10% PBS/EtOH. This indicates that the new "Ga III (Bn-NODP)" moiety is a considerably superior fluoride binding scaffold than the previously reported [Ga 18 F(Bn-NODA)] (Bn-NODA = 1-benzyl-4,7-dicarboxylate-1,4,7-triazacyclononane), which undergoes rapid and complete hydrolysis in PBS/EtOH (refer to Chem. Eur. J. 2015 , 21 , 4688-4694).