Indium(III) and Gallium(III) Complexes of Bis(aminoethanethiol) Ligands with Different Denticities:  Stabilities, Molecular Modeling, and in Vivo Behavior

Abstract

Complexes of Ga(III) and In(III) radionuclides are widely used in diagnostic imaging. In this study, the following ligands of denticities 4, 5, and 6 respectively were prepared: N,N'-bis-(2,2-dimethyl-2-mercaptoethyl) ethylenediamine (4SS), 1-carboxy-N-N'-bis(2,2-dimethyl-2- mercaptoethyl)ethylenediamine (5SS), and N,N'-bis(2,2- dimethyl-2-mercaptoethyl)ethylenediamine-N,N'-diacetic acid (6SS). Syntheses of the two new ligands, 5SS and 6SS, are described. Equilibrium constants for their In(III) and Ga(III) complexes were determined by both direct and ligand-competitive potentiometric methods. The formation constant (KML = [ML]/[M][L]) of In(III)--6SS in 0.100 M KNO3 at 25.0 degrees C is 10(39.8), and its pM at physiological pH (7.4 with 100% excess of the ligand) is 30.9. These values are higher than those of any other previous reported ligand for In(III). The stability constants of the complexes of 4SS, 5SS, 6SS, and the analogous ligand EDDASS, N,N'-bis(2-mercaptoethyl) ethylenediamine-N,N'-diacetic acid, which does not contain gem-dimethyl groups, are compared. The thermodynamic stabilities of the In(III) complexes of all ligands except 6SS are greater than those of the corresponding Ga(III) complexes. The presence of the geminal dimethyl groups in 6SS increased the stability of the Ga(III) and In(III) complexes over those of EDDASS. The effects of the gem-dimethyl groups on complex stabilities are explained by molecular modeling. The serum stabilities and biodistributions out to 1 h postinjection of 67/68Ga and 111In chelates of 4SS, 5SS, and 6SS were measured and compared with those of EDDASS. The 67/68Ga- and 111In-ligand complexes with more donor atoms showed were more stable in serum, both in vitro and in vivo. The biodistributions of the 67/68Ga- and 111In-ligand complexes exhibited distinct trends. None of the 67/68Ga- and 111In-chelates demonstrated significant heart or brain uptake. The majority of uptake for all compounds was in the liver and kidney. The degree of clearance through the liver corresponded to the thermodynamic stability of the complex. Correlations between in vivo behavior, molecular modeling data, and thermodynamic stability of the complexes are discussed.

Equilibrium, Kinetic and Structural Properties of Gallium(III) and Some Divalent Metal Complexes Formed with the New DATAm and DATA5m Ligands

“…In the complexes of AAZTA, three N-and four carboxylate O-atoms can simultaneously bind the metal ion. [11][12][13] Removing one carboxylate group will evidently affect the equilibrium, kinetic and structural properties of the metal complexes formed with DATA m and DATA 5m ligands. Indeed, the DATA m ligand has been shown to form a well-defined octahedral Ga III -complex by X-ray crystallography.…”

“…Under such conditions, the ligand exchange reaction can be treated as a pseudo-firstorder process and the rate of the reaction can be expressed by Equation (10). By taking into account the molar absorptivity of Ga(sTf) (ε 246 =13800 cm -1 M -1 ), [17] the rate constants (k d ) were calculated from the slope of the kinetic curves (ΔAbs/Δt, Figures S11 and S12) with Equation (11) (the middle term in Equation (11) has been replaced by 1/ε Ga(sTf) ). The slope of the kinetic curves were considered up to 30 % conversion, in order to be sure of the Ga(sTf)-complex formation.…”

“…The established diagnostic power of the Positron Emission Tomography (PET) technique in MI and the increasing availability of new biological targeting vectors have led to the design and testing of a large number of radiopharmaceuticals in oncology, cardiology, neurology, and infectious diseases. [1] The introduction of radionuclides like 3 H, 11 C or 18 F to biological targeting vectors needs time consuming synthesis. Taking the half-life of these nuclides into account, this is the main disadvantage for these radioisotopes in means of preparation and examination of their derivatives.…”

“…EDDA-SS, TACN-TM). [11] The coordination of Ga 3+ with several different ligands has been thoroughly investigated, starting from the screening work of Martell [6a,6b] and followed, in the last two decades, by the design and development of novel and improved Ga III -complexes in order to prevent the transmetallation reaction with endogeneous metal ions (Cu 2+ , Zn 2+ , Ca 2+ ) or transchelation reactions with proteins such as transferrin. [12] It is well established that macrocyclic chelators such as 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), either free or conjugated to peptides, form thermodynamically stable and kinetically inert complexes with 68 Ga. [12][13][14] However, the efficient labeling of DOTA and NOTA ligands with 68 Ga isotope requires a large excess of ligand (>1000 fold) and high temperature (95°C) which tend to denaturate the biologically active proteins.…”

Tumor Specific Imaging Using Tc-99m and Ga-68 Labeled Radiopharmaceuticals

“…Tc efficiently with high radiochemical purity and the preparation remains stable for several hours [12][13][14][15][16][17][18][19][20][21][22].…”