Selectivity of Potentially Hexadentate Amine Phenols for Ga³⁺ and In³⁺ in Aqueous Solution^,

Abstract

A new series of linear N4O2 amine phenols (H2 badd, H2 Brbadd, and H2 Clbadd) based on N,N‘-bis(3-aminopropyl)ethylenediamine (tnentn) were prepared and characterized by spectroscopic techniques. Monocationic hexadentate metal complexes with the tnentn-based amine phenols were obtained from the reactions of Ga3+ and In3+ with the linear amine phenol in the presence of a weak base (acetate). The molecular structure of [Ga(Brbadd)]ClO4 has been determined by X-ray crystallography; crystals of [Ga(Brbadd)][ClO4] (C22H30Br2ClGaN4O6) are orthorhombic: a = 12.462(1) Å, b = 21.835(2) Å, c = 9.961(2) Å, Z = 4, space group P212121. The structure was solved by the Patterson method and was refined by full-matrix least-squares procedures to R = 0.031 (R w = 0.029) for 1924 reflections with I ≥ 3σ(I). The Ga3+ ion is coordinated in a distorted octahedral geometry by an N4O2 donor atom set. The four nitrogen atoms of the tetraamine backbone form the equatorial plane of the octahedron, and the two phenolate oxygen atoms are coordinated trans to each other. Water-soluble 1,10-bis(2-hydroxy-5-sulfonylbenzyl)-1,4,7,10-tetraazadecane (H6 Sbad 2+), 1,12-bis(2-hydroxybenzyl-5-sulfonylbenzyl)-1,5,8,12-tetraazadodecane (H6 Sbadd 2+), and N,N‘-bis-(2-hydroxy-5-sulfonylbenzyl)-N,N‘-bis(2-methylpyridyl)ethylenediamine (H6 Sbbpen 2+) were also prepared and characterized; potentiometric titrations of these three ligands, in the absence and presence of Ga3+ and In3+, were performed to determine deprotonation constants of the ligands and the thermodynamic stabilities of Ga and In amine phenol complexes. The formation constants of the Ga3+ and In3+ complexes with Sbad 4- (Ga3+, log β = 28.33(8); In3+, log β = 24.54(2)), Sbadd 4- (Ga3+, log β = 28.27(5); In3+, log β = 24.56 (5)), and Sbbpen 4- (Ga3+, log β = 35.33(8); In3+, log β = 34.85(5)) were obtained. All six of the Ga and In hexadentate amine phenol complexes were found to be very stable in aqueous solution. With the exception of [In(Sbadd)]-, all the complexes were calculated to be thermodynamically stable with respect to demetalation by transferrin at physiological pH. The linear amine phenols showed a selectivity for Ga3+ over In3+, while the Sbbpen 4- derivative was indiscriminate in binding the Ga3+ and In3+ ions.

Bifunctional coupling agents for radiolabeling of biomolecules and target-specific delivery of metallic radionuclides

“…Due to their high charge density, Ga(III) and In(III) prefer hard donors, such as amine-N and carboxylate-O atoms. Because of the small size, Ga (III) is often six-coordinated [198][199][200][201][202][203]. Both Ga(III) and In(III) are similar to Fe(III) with respect to their coordination chemistry and biological properties.…”

Chelator free gallium-68 radiolabelling of silica coated iron oxide nanorods via surface interactions

“…[15][16][17] Iron-oxide based nanorods (NRs) are less common but may offer advantages, such as improved MRI contrast [18][19][20] and improved properties as drug delivery vehicles. 26,27 Incorporation of 68 Ga into a targeting vector is generally achieved by the use of bifunctional chelating agents (BCAs), molecules containing a chelating moiety responsible for trapping 68 Ga in a stable in vivo form, functionalised with a reactive group allowing its conjugation to a bioactive molecule, protein or peptide. 22,23 In aqueous solution and at physiological pH, 68 Ga is exclusively in the oxidation state +3, thus most synthetic procedures are carried out in the presence of weakly coordinating ligands such as citrate, acetate or oxalate at low pH in order to avoid the formation of insoluble Ga(OH) 3 and soluble Ga(OH) 4 − , both of which dramatically slow the kinetics of complex formation.…”

Recent advances in chelator design and labelling methodology for 68Ga radiopharmaceuticals

“…Most synthetic procedures are carried out in the presence of weakly coordinating ligands such as citrate, acetate or oxalate to avoid the formation of insoluble Ga(OH) 3 and soluble Ga(OH) 4 − , both of which dramatically reduce the kinetics of complex formation . Gallium(III) generally forms six coordinate complexes and is classified as hard Lewis acidic and therefore binds to hard Lewis base donor atoms such as nitrogen and oxygen, which are present in the routinely used BFCs . Acyclic BFCs are generally less kinetically inert and thermodynamically stable than their macrocyclic counterparts but have the advantage of faster metal ion binding kinetics .…”