N,N′-Ethylene-di-l-Cysteine (EC) complexes of Ga(III) and In(III): Molecular modeling, thermodynamic stability and in vivo studies
TL;DR: A molecular mechanics evaluation of the Ga- and In-EC complexes support the thermodynamic results and derivatives of EC may have applications as bifunctional chelates for 111In-labeled proteins and peptides.
About: This article is published in Nuclear Medicine and Biology.The article was published on 1995-02-01. It has received 48 citations till now. The article focuses on the topics: Stability constants of complexes & Chemical stability.
Citations
More filters
TL;DR: In this paper, a variety of mono-and bifunctional chelators have been developed which allow the formation of stable (68)Ga(3+)complexes and convenient coupling to biomolecules.
Abstract: PET (positron emission tomography) is a powerful diagnostic and imaging technique which requires short-lived positron emitting isotopes. The most commonly used are accelerator-produced (11)C and (18)F. An alternative is the use of metallic positron emitters. Among them (68)Ga deserves special attention because of its availability from long-lived (68)Ge/(68)Ga generator systems which render (68)Ga radiopharmacy independent of an onsite cyclotron. The coordination chemistry of Ga(3+) is dominated by its hard acid character. A variety of mono- and bifunctional chelators have been developed which allow the formation of stable (68)Ga(3+)complexes and convenient coupling to biomolecules. (68)Ga coupling to small biomolecules is potentially an alternative to (18)F- and (11)C-based radiopharmacy. In particular, peptides targeting G-protein coupled receptors overexpressed on human tumour cells have shown preclinically and clinically high and specific tumour uptake. Kit-formulated precursors along with the generator may be provided, similar to the (99)Mo/(99m)Tc-based radiopharmacy, still the mainstay of nuclear medicine.
311 citations
TL;DR: Fundamental concepts of drug design and applications are introduced, with particular emphasis on bifunctional chelators (BFCs), which ensure secure consolidation of the radiometal and targeting vector and are integral for optimal drug performance.
Abstract: Radiometals possess an exceptional breadth of decay properties and have been applied to medicine with great success for several decades. The majority of current clinical use involves diagnostic procedures, which use either positron-emission tomography (PET) or single-photon imaging to detect anatomic abnormalities that are difficult to visualize using conventional imaging techniques (e.g., MRI and X-ray). The potential of therapeutic radiometals has more recently been realized and relies on ionizing radiation to induce irreversible DNA damage, resulting in cell death. In both cases, radiopharmaceutical development has been largely geared toward the field of oncology; thus, selective tumor targeting is often essential for efficacious drug use. To this end, the rational design of four-component radiopharmaceuticals has become popularized. This Review introduces fundamental concepts of drug design and applications, with particular emphasis on bifunctional chelators (BFCs), which ensure secure consolidation of the radiometal and targeting vector and are integral for optimal drug performance. Also presented are detailed accounts of production, chelation chemistry, and biological use of selected main group and rare earth radiometals.
257 citations
TL;DR: This review summarizes some of the developments of metal complexes and metal-complex-bioconjugates for the diagnosis of disease states that have occurred over the past 10 years, and demonstrates the significant progress made in the field of coordination chemistry as it applies to the development of diagnostic imaging agents.
238 citations
TL;DR: The 67/68Ga- and 111In-ligand complexes with more donor atoms showed were more stable in serum, both in vitro and in vivo, and the effects of the gem-dimethyl groups on complex stabilities are explained by molecular modeling.
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.
94 citations
Patent•
07 Nov 2003TL;DR: In this paper, a new labeling strategy employing 99m Tc chelated with ethylenedicysteine (EC) was proposed for tissue-specific disease imaging, which can also be used as a prognostic tool or as a tool to deliver therapeutics to specific sites within a mammalian body.
Abstract: The invention provides, in a general sense, a new labeling strategy employing 99m Tc chelated with ethylenedicysteine (EC). EC is conjugated with a variety of ligands and chelated to 99m Tc for use as an imaging agent for tissue-specific diseases. The drug conjugates of the invention may also be used as a prognostic tool or as a tool to deliver therapeutics to specific sites within a mammalian body. Kits for use in tissue-specific disease imaging are also provided.
84 citations
References
More filters
TL;DR: The effective ionic radii of Shannon & Prewitt [Acta Cryst. (1969), B25, 925-945] are revised to include more unusual oxidation states and coordinations as mentioned in this paper.
Abstract: The effective ionic radii of Shannon & Prewitt [Acta Cryst. (1969), B25, 925-945] are revised to include more unusual oxidation states and coordinations. Revisions are based on new structural data, empirical bond strength-bond length relationships, and plots of (1) radii vs volume, (2) radii vs coordination number, and (3) radii vs oxidation state. Factors which affect radii additivity are polyhedral distortion, partial occupancy of cation sites, covalence, and metallic character. Mean Nb5+-O and Mo6+-O octahedral distances are linearly dependent on distortion. A decrease in cation occupancy increases mean Li+-O, Na+-O, and Ag+-O distances in a predictable manner. Covalence strongly shortens Fe2+-X, Co2+-X, Ni2+-X, Mn2+-X, Cu+-X, Ag+-X, and M-H- bonds as the electronegativity of X or M decreases. Smaller effects are seen for Zn2+-X, Cd2+-X, In2+-X, pb2+-X, and TI+-X. Bonds with delocalized electrons and therefore metallic character, e.g. Sm-S, V-S, and Re-O, are significantly shorter than similar bonds with localized electrons.
51,997 citations
TL;DR: In this paper, a molecular mechanics force field implemented in the Sybyl program is described along with a statistical evaluation of its efficiency on a variety of compounds by analysis of internal coordinates and thermodynamic barriers.
Abstract: A molecular mechanics force field implemented in the Sybyl program is described along with a statistical evaluation of its efficiency on a variety of compounds by analysis of internal coordinates and thermodynamic barriers. The goal of the force field is to provide good quality geometries and relative energies for a large variety of organic molecules by energy minimization. Performance in protein modeling was tested by minimizations starting from crystallographic coordinates for three cyclic hexapeptides in the crystal lattice with rms movements of 0.019 angstroms, 2.06 degrees, and 6.82 degrees for bond lengths, angles, and torsions, respectively, and an rms movement of 0.16 angstroms for heavy atoms. Isolated crambin was also analyzed with rms movements of 0.025 angstroms, 2.97 degrees, and 13.0 degrees for bond lengths, angles, and torsions respectively, and an rms movement of 0.42 angstroms for heavy atoms. Accuracy in calculating thermodynamic barriers was tested for 17 energy differences between conformers, 12 stereoisomers, and 15 torsional barriers. The rms errors were 0.8, 1.7, and 1.13 kcal/mol, respectively, for the three tests. Performance in general purpose applications was assessed by minimizing 76 diverse complex organic crystal structures, with and without randomization by coordinate truncation, with rms movements of 0.025 angstroms, 2.50 degrees, and 9.54 degrees for bond lengths, angles and torsions respectively, and an average rms movement of 0.192 angstroms for heavy atoms.
2,641 citations
1,040 citations
Book•
01 Jan 1992
TL;DR: In this article, the authors present a complete metal complex data base with linear stability constants and species concentrations of complex systems, including a mixed-ligand binuclear dioxygen system nonaqueous solvents complex multicomponent systems equilibrium with solid phases equilibrium involving hydrolytic species species distributions of hydroxo and fluoro complexes of AI(III).
Abstract: Part 1 Introduction: stability constants - early work recent developments historical evolution of computational methods purpose of this book. Part 2 Equilibrium constants, protonation constants, formation constants: concentration constants and activity constants conventions employment for expressing equilibrium constants equilibrium constants and stability constants for EDTA species distribution curves. Part 3 Experimental methods for measuring equilibrium constants: methods available potentiometric pH measurements displacement methods pH and p[H]measurement of metal complex equilibria: materials, the reaction mixture calibration of the potentiometric apparatus the experimental runs computation of stability constants.Part 4 Common errors and their elimination or minimization: measurements errors calibration and electrode care reagents equilibrium measurements calculations selection of the model. Part 5 Examples of stability constant determination: iminodiacetic acid (IDA) procedure for IDA C-BISTREN procedure for C-BISTREN. Part 6 Macroscopic and microscopic constants: some definitions and concepts ionization of tyrosine microscopic protonation equilibria of DOPA general comments and conclusions. Determination of stability constants and species concentrations of complex systems: a mixed-ligand binuclear dioxygen system non-aqueous solvents complex multicomponent systems equilibrium with solid phases equilibrium involving hydrolytic species species distributions of hydroxo and fluoro complexes of AI(III). Part 7 Critical stability constants and their selection: general criteria examples of critical data selection need for additional critical constants. Part 8 Development of a complete metal complex data base: introduction linear stability. constant correlations estimation of estability constants not measured experimentally metal speciation in sea water with and without added ligands.
962 citations
TL;DR: Thermodynamic binding constants for gallium complexation at the two specific metal binding sites of human serum transferrin at pH 7.4 and 5 mM NaHCO3 have been determined by UV difference spectroscopy and are discussed in relation to the thermodynamics of transferrin binding of Fe3+.
Abstract: Gallium-67 is widely used as an imaging agent for tumors and inflammatory abscesses. It is well established that Ga3+ travels through the circulatory system bound to the serum iron transport protein transferrin and that this protein binding is an essential step in tumor localization. However, there have been conflicting reports on the magnitude of the gallium-transferrin binding constants. Therefore, thermodynamic binding constants for gallium complexation at the two specific metal binding sites of human serum transferrin at pH 7.4 and 5 mM NaHCO3 have been determined by UV difference spectroscopy. The conditional constants calculated for 27 mM NaHCO3 are log K1 = 20.3 and log K2 = 19.3. These results are discussed in relation to the thermodynamics of transferrin binding of Fe3+ and to previous reports on gallium binding. The strength of transferrin complexation is also compared to that of a series of low molecular weight ligands by using calculated pM values (pM = -log [Ga-(H2O)6]) to express the effective binding strength at pH 7.4.
300 citations