One-pot radioiodination of aryl amines via stable diazonium salts: preparation of 125I-imaging agents

An operationally simple, one-pot, two-step tandem procedure that allows the incorporation of radioactive iodine into aryl amines via stable diazonium salts is described. The mild conditions are tolerant of various functional groups and substitution patterns, allowing late-stage, rapid access to a wide range of 125I-labelled aryl compounds and SPECT radiotracers

Late stage iodination of biologically active agents using a one-pot process from aryl amines

A simple and effective one-pot tandem procedure that generates aryl iodides from readily available aryl amines via stable diazonium salts has been developed. The operationally simple procedure and mild conditions allow late-stage iodination of a wide range of aryl compounds bearing various functional groups and substitution patterns. A novel synthetic strategy involving the preparation of nitroaryl compounds followed by a chemoselective tin(II) dichloride reduction and the use of the one-pot diazotisation–iodination transformation was also developed. The general applicability of this approach was demonstrated with the preparation of a number of medicinally important compounds including CNS1261, a SPECT imaging agent of the N-methyl-D-aspartate (NMDA) receptor and IBOX, a compound used to detect amyloid plaques in the brain

Triaza-macrocyclic complexes of aluminium, gallium and indium halides: fast 18F and 19F incorporation via halide exchange under mild conditions in aqueous solution

Rapid and complete fluorination of the complexes [MCl3(L)] (L = Me3-tacn, BzMe2-tacn, M = Al, Ga, In) occurs at room temperature via reaction of a MeCN solution of the complex with 3 mol. equivs. of KF in water. The Ga and In complexes are also readily fluorinated using R4NF (R = Me or nBu) in MeCN solution, whereas no reaction occurs with the Al species under these conditions. The distorted octahedral fac-trifluoride coordination at M is confirmed in solution by multinuclear (19F, 27Al, 71Ga and 115In) NMR spectroscopic studies, leading to sharp resonances with 19F-71Ga and 19F-115In couplings evident. The [MF3(L)] are extremely stable in aqueous solution and at low pH; they crystallise as tetrahydrates, [MF3(Me3-tacn)]·4H2O, with extended H-bonding networks formed through both F···H-O and O···H-O contacts. [InF3(BzMe2-tacn)]·1.2H2O also shows intermolecular F···H-O hydrogen bonding contacts. The prospects for developing this coordination chemistry further to take advantage of the high metal-fluoride bond energies to enable rapid, late-stage fluorination of large macromolecules under mild conditions for PET imaging applications in nuclear medicine are discussed. This work also demonstrates that F-18 radiolabelling to form [F-18] [GaF3(BzMe2-tacn)] is effected readily at room temperature in aqueous MeCN over 30-60 mins on addition of 2.99 mol equivs. of [19F]-KFaq and 0.4 mL [18F]-KFaq (100 – 400 MBq) to [GaCl3(BzMe2-tacn)] with ca. 30% incorporation

Radiofluorination of a pre-formed gallium(III) aza-macrocyclic complex: towards next-generation positron emission tomography (PET) imaging agents

As part of a study to investigate the factors influencing the development of new, more effective metal-com-plex-based positron emission tomography (PET) imaging agents, the distorted octahedral complex, [GaCl(L)]·2HO has been prepared by reaction of 1-benzyl-1,4,7-triazacyclono-nane-4,7-dicarboxylic acid hydrochloride (HL·HCl) with Ga(NO)·9HO, which is a convenient source of GaIII for reactions in water. Spectroscopic and crystallographic data for [GaCl(L)]·2HO are described, together with the crystal structure of [GaCl(L)]·MeCN. Fluorination of this complex by Cl/ F- exchange was achieved in high yield by treatment with KF in water at room temperature over 90 minutes, although the reaction was complete in approximately 30 minutes if heated to 80 °C, giving [GaF(L)]·2HO in good yield. The same complex was obtained by hydrothermal synthesis from GaF·3HO and LiL, and has been characterised by singlecrystal X-ray analysis, IR, 1H and 19F{1H} NMR spectroscopy and ESI + MS.Radiofluorination of the pre-formed [GaCl(L)]·2 HO has been demonstrated on a 210 nanomolar scale in aqueous NaOAc at pH 4 by using carrier-free F , leading to 60-70% F-incorporation after heating to 80 8C for 30 minutes. The resulting radioproduct was purified easily by using a solid-phase extraction (SPE) cartridge, leading to 98-99% radiochemical purity. The [Ga F(L)] is stable for at least 90 minutes in 10% EtOH/NaOAc solution at pH 6, but defluorinates over this time scale at pH of approximately 7.5 in phosphate buffered saline (PBS) or human serum albumin (HSA). The subtle role of the Group 13 metal ion and coligand donor set in influencing the pH dependence of this system is discussed in the context of developing potential new imaging agents for PET

[AlCl3(BnMe2-tacn)] – a new metal chelate scaffold for radiofluorination by Cl/F exchange

Radiofluorination of a 2.63 μM solution (pH 4, NaOAc buffer) of [AlCl3(BnMe2-tacn)] via treatment with 2.99 mol. equiv. of [19F]KF doped with cyclotron-produced [18F]F− target water, with heating to 80–100 °C for 1 h, gives up to 24% 18F incorporation. SPE purification of the [Al19F218F(BnMe2-tacn)] radio-product gives >99% RCP, with excellent stability (>99% RCP after 3 h)

Hydrothermal synthesis of Group 13 metal trifluoride complexes with neutral N-donor ligands

The reactions of the hydrated Group 13 fluorides, MF3·3H2O (M = Al, Ga or In) with 2,2?:6?,2??-terpyridyl, 2,2?-bipyridyl or 1,10-phenanthroline under hydrothermal conditions (180 °C/15 h) produced high yields of the complexes [MF3(terpy)]·3H2O, [MF3(bipy)(OH2)]·2H2O and [MF3(phen)(OH2)]. X-Ray crystal structures of [M?F3(terpy)]·3H2O (M? = Al or Ga), [M?F3(bipy)(OH2)]·2H2O and [GaF3(phen)(OH2)] show that all of them contain distorted octahedral geometries at the metal with mer-trifluoride coordination. Extensive H-bonding (FH–OH) links the molecules. The complexes have been further characterised by microanalysis, IR, 1H, 19F{1H} and 27Al NMR spectroscopy. In contrast, reactions of the trifluorides with the acyclic triamine, N,N,N?,N?,N??-pentamethyldiethylenetriamine, under similar hydrothermal conditions results in cleavage of the triamine and ring-closure to form the 1,1,4-trimethylpiperazinium cation, [?Me2N(CH2)2NMe(CH2)2]+, with fluorometallate anions, and confirmed by X-ray analysis of [?Me2N(CH2)2NMe(CH2)2]2[Al2F8(OH2)2]·2H2O. The strongly H-bonded [GaF3(terpy)]·3H2O was also obtained by Cl/F exchange from [GaCl3(terpy)] and [NBu4]F or [K(2,2,2-crypt)]F. Crystallisation of a mixture of [NH4][PF6] and [GaF3(terpy)]·3H2O from aqueous solution produced the edge-bridged cationic complex, [{Ga(terpy)F}2(?-F)2][PF6]2. The synthesis of the more sterically bulky [GaCl3(tBu3-terpy)] (tBu3-terpy = 4,4?4??-tris-tBu-2,2?:6?,2??-terpyridyl) and the crystal structure of [GaCl2(tBu3-terpy)][GaCl4], which contains a trigonal bipyramidal cation, are also reported

Rapid aqueous late-stage radiolabelling of [GaF3(BnMe2-tacn)] by 18F/19F isotopic exchange – towards new PET imaging probes

A simple and rapid method for 18F radiolabelling of [GaF3(BnMe2-tacn)] by 18F/19F isotopic exchange is described. Using MeCN:H2O or EtOH:H2O (75:25) and 18F(aq) (up to 200 MBq) with heating (80 C, 10 mins.), gives 66±4% 18F incorporation at 268 nM concentration and 37±5% 18F incorporation at even lower (27 nM) concentration, without the need for a Lewis acid promoter. An SPE purification method has been established, giving 99% radiochemical purity (RCP) of [Ga18F19F(BnMe2-tacn)] in an EtOH/H2O mixture

[GaF3(BzMe2-tacn)] – a neutral ‘metalloligand’ towards alkali metal and ammonium cations in water

The neutral complex, [GaF3(L)] (L = 1-benzyl-4,7-dimethyl-1,4,7-triazacyclononane, BzMe2-tacn), acts as a ‘metalloligand’ to Na+, K+ and [NH4]+ cations in aqueous solution, forming supramolecular assemblies containing significant Na/K–F and H3N+H⋯F coordination. κ1-[BF4]− and κ2-[PF6]− coordination is also evident to Na+ and K+, respectively