Synthesis and properties of metal trifluoride complexes with amide-functionalised tacn macrocycles and radiofluorination of [GaF3(L1)] by 18F/19F isotopic exchange.

Three amide-functionalised tacn macrocyclic derivatives (tacn = 1,4,7-triazacyclononane) are reported, two tris-amide derivatives, L1 containing three -CH2C(O)NHPh pendant arms, L2 containing three -CH2CH2C(O)NHiPr pendant arms, and one mono-amide, L3, containing iPr groups on two of the tacn amine functions and a single -CH2C(O)NHPh function on the third. The reactions of these new ligands towards [MF3(dmso)(OH2)2] (M = Al, Ga) and towards FeF3·3H2O in alcoholic solution afford the complexes [MF3(L)] (L = L1-L3) in good yields as powdered solids. These complexes are characterised by IR and multinuclear NMR spectroscopy (diamagnetic species only) and mass spectrometry. [GaF3(L1)], [GaF3(L3)] and [FeF3(L3)] are also characterised by single crystal X-ray analysis. The corresponding reactions involving [InF3(dmso)(OH2)2] yield mixtures of products (along with F-), consistent with the M-F bond strengths decreasing as group 13 is descended. A few crystals of the target complex, [InF3(L2)], were also obtained from one such reaction. All of the complexes adopt fac-octahedral coordination via the amine N-donor atoms and retain the three fluoride ligands both in solution and in the solid state. Extensive intramolecular hydrogen-bonding involving the amide NH pendant groups and the MF3 moieties is evident in the crystal structures. In the isostructural [MF3(L3)] (M = Ga, Fe) complexes the head-to-tail C(O)NH⋯F H-bonded dimers observed in the solid state resemble those found frequently in organic compounds and that form the cornerstone of many supramolecular assemblies. This is consistent with the MF3 fragments being strong H-bond acceptors. Radiofluorination of [GaF3(L1)] by 18F/19F isotopic exchange in MeOH at 3 µmol mL-1 precursor concentration and using aqueous [18F]F- in target water (75% : 25%) with gentle heating (80 °C, 10 min) gave ca. 20% radiochemical yield of [Ga18FF2(L1)]. In contrast, no 18F incorporation occurs with [GaF3(L3)] under any of the conditions explored.

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 18F Binding.

With the aim of obtaining improved molecular scaffolds for 18F 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, H2(Bn-NODP) (1-benzyl-4,7-phenylphosphinic acid-1,4,7-triazacyclononane), which is isolated as its protonated form, H2(Bn-NODP)·2HCl·4H2O, at low pH (HClaq), its disodium salt, Na2(Bn-NODP)·5H2O at pH 12 (NaOHaq), or the neutral H2(Bn-NODP) under mildly basic conditions (Et3N). A crystal structure of H2(Bn-NODP)·2HCl·H2O confirmed the ligand's identity. The mononuclear [GaCl(Bn-NODP)] complex was prepared by treatment of either the HCl or sodium salt with Ga(NO3)3·9H2O or GaCl3, while treatment of H2(Bn-NODP)·2HCl·4H2O with FeCl3 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 N3O2 donor set, with the halide ligand completing a distorted octahedral geometry; this is further confirmed through a crystal structure analysis on [GaF(Bn-NODP)]·4H2O. 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/NaOAcaq (Ga) or EtOH (Ga or Fe; i.e. without buffer) with 18F- 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 [Fe18F(n-NODP)] is unstable (loss of 18F-) in both H2O/EtOH and PBS/EtOH (PBS = phosphate buffered saline), the [Ga18F(Bn-NODP)] radioproduct shows excellent stability, RCP = 99% at t = 4 h (RCP = radiochemical purity) when formulated in 90%:10% H2O/EtOH and ca. 95% RCP over 4 h when formulated in 90%:10% PBS/EtOH. This indicates that the new "GaIII(Bn-NODP)" moiety is a considerably superior fluoride binding scaffold than the previously reported [Ga18F(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).

Tin(IV) fluoride complexes with neutral phosphine coordination and comparisons with hard N- and O-donor ligands.

The reactions of trans-[SnF4(PMe3)2] with one, two or three equivalents of Me3SiO3SCF3 (TMSOTF), respectively, in anhydrous CH2Cl2 form six-coordinate [SnF4-n(PMe3)2(OTf)n] (n = 1-3), which have been characterised by microanalysis, IR and multinuclear NMR (1H, 19F{1H}, 31P{1H} and 119Sn) spectroscopy. The crystal structure of [SnF3(PMe3)2(OTf)] reveals the three fluorines are in a mer-arrangement with mutually trans PMe3 ligands. The multinuclear NMR spectra confirm this structure is retained in solution, and show that [SnF2(PMe3)2(OTf)2] has trans-phosphines, while [SnF(PMe3)2(OTf)3] has trans PMe3 groups and hence mer-triflate ligands. The [SnF4-n(PMe3)2(OTf)n] are unstable in solution and the decomposition products include [Me3PF]+ and the tin(II) complexes [Sn(PMe3)2(OTf)2] and [Sn3F5(OTf)], both of the latter identified by their crystal structures. The reaction of trans-[SnF4(PiPr3)2] containing the bulkier phosphine, with one and two equivalents of TMSOTf produced unstable mono- and bis-triflates, which the NMR data also suggest contain weakly coordinated triflate, [SnF3(PiPr3)2(OTf)] and [SnF2(PiPr3)2(OTf)2], again with axial phosphines, although some OTf dissociation from the former to give [SnF3(PiPr3)2]+ may occur in solution at room temperature. The new phosphine complexes of SnF4, trans-[SnF4(PiPr3)2] and (cis) [SnF4(κ2-triphos)] (triphos = CH3C(CH2PPh2)3) have also been fully characterised, including the crystal structure of [SnF4(κ2-triphos)]. Attempts to promote P3-coordination by further treatment of this complex with TMSOTf were unsuccessful. The [SnF4(L)2] (L = dmso, py, pyNO, DMF, OPPh3) complexes, which exist as mixtures of cis and trans isomers, react with one equivalent of TMSOTf, followed by addition of one equivalent of L, to form the ionic [SnF3(L)3][OTf] complexes, which were characterised by microanalysis, IR and multinuclear NMR spectroscopy. In nitromethane solution they are a mixture of mer and fac isomers based upon multinuclear NMR data (1H, 19F{1H}, 119Sn). Reaction of [SnF4(OPPh3)2] with two equivalents of TMSOTf and further OPPh3 produced [SnF2(OPPh3)4][OTf]2, which is a mixture of cis and trans isomers in solution. The crystal structure of [SnF2(OPPh3)4][OTf]2 confirms the trans isomer in the solid state, with the triflate ionic. These complexes are rare examples of fluorotin(IV) cations with neutral monodentate ligands.

FASTlab Radiosynthesis of the 18 F-labelled HER2-binding Affibody molecule [18 F]GE-226.

An 18 F-labelled human epidermal growth factor receptor (HER2) receptor binding radiotracer is a potential tool to non-invasively identify HER2 positive tumour lesions in subjects with recurrent metastatic breast cancer. Having explored the manual radiochemistry to conjugate the Affibody molecule ZHER2:2891 with [18 F]4-fluorobenzaldehyde, we have developed and optimised a full protocol for the automated GE FASTlab synthesiser. Our chemometric model predicted the best radiochemical purity for a short conjugation time (2.8 minutes), a low temperature (65°C), and a medium Affibody molecule precursor amount (5.5 mg). Under these optimised conditions, [18 F]GE-226 was produced after solid-phase extraction purification with activity yield of 30% ± 7 (n = 18) and a radiochemical purity of 94% ± 2 (n = 18). The synthesis and purification was complete after 43 minutes and provided apparent molar activities of 12 to 30 GBq/µmol (n = 12) at the end of synthesis.

Influence of transport line material on the molar activity of cyclotron produced [18F]fluoride.

INTRODUCTION: Production of fluorine-18-labeled radiopharmaceuticals is always associated with the varying levels of the same compound containing stable fluorine-19. In practice, this affects the molar activity (Am), defined as amount of radioactivity divided by the molar quantity (Bq/mol). We have focused on studying how the material of the transport tubing connecting the cyclotron target chamber to the synthesis device affects the concentration of fluoride in the water arriving to the reaction vessel and subsequently the Am of the fluorine-18 labeled radiopharmaceuticals produced. METHODS: Batches of irradiated and non-irradiated water were analyzed for fluoride content after being transported via non-fluorinated (PEEK, PP) and fluorinated (PTFE, ETFE) tubing or using no tubing at all. Am for the [18F]fluoride was determined and compared with the Am of [18F]fluciclatide, synthesized from the same [18F]fluoride containing batches of water. RESULTS: Significantly higher concentrations of fluoride were seen in irradiated water that was transported in fluorinated tubing compared to non-irradiated water transported in tubing of the same material. This elevation of fluoride concentration is presumably caused by the interaction of ionizing radiation with the fluorinated tubing used between the target chamber and hot cell. Likewise, a significant difference was seen for PEEK tubing (non-fluorinated). This could be due to the fact that fluorine containing compounds are used in the manufacture of PEEK. When using fluorinated tubing for transport of the irradiated water, the resulting fluciclatide concentrations were significantly higher compared to when using non-fluorinated tubing. No significant difference was seen between fluciclatide concentrations when PTFE or ETFE tubing was compared to each other. Using no tubing resulted in lowest fluciclatide concentration. CONCLUSIONS: Fluorinated tubing is a source of stable fluoride, and Am can be increased by using non-fluorinated transport tubing. Of all the tubing materials studied PP is preferred.

Automation of [(18) F]fluoroacetaldehyde synthesis: application to a recombinant human interleukin-1 receptor antagonist (rhIL-1RA).

[(18) F]Fluoroacetaldehyde is a biocompatible prosthetic group that has been implemented pre-clinically using a semi-automated remotely controlled system. Automation of radiosyntheses permits use of higher levels of [(18) F]fluoride whilst minimising radiochemist exposure and enhancing reproducibility. In order to achieve full-automation of [(18) F]fluoroacetaldehyde peptide radiolabelling, a customised GE Tracerlab FX-FN with fully programmed automated synthesis was developed. The automated synthesis of [(18) F]fluoroacetaldehyde is carried out using a commercially available precursor, with reproducible yields of 26% ± 3 (decay-corrected, n = 10) within 45 min. Fully automated radiolabelling of a protein, recombinant human interleukin-1 receptor antagonist (rhIL-1RA), with [(18) F]fluoroacetaldehyde was achieved within 2 h. Radiolabelling efficiency of rhIL-1RA with [(18) F]fluoroacetaldehyde was confirmed using HPLC and reached 20% ± 10 (n = 5). Overall RCY of [(18) F]rhIL-1RA was 5% ± 2 (decay-corrected, n = 5) within 2 h starting from 35 to 40 GBq of [(18) F]fluoride. Specific activity measurements of 8.11-13.5 GBq/µmol were attained (n = 5), a near three-fold improvement of those achieved using the semi-automated approach. The strategy can be applied to radiolabelling a range of peptides and proteins with [(18) F]fluoroacetaldehyde analogous to other aldehyde-bearing prosthetic groups, yet automation of the method provides reproducibility thereby aiding translation to Good Manufacturing Practice manufacture and the transformation from pre-clinical to clinical production.