Theoretical insight into M²⁺/M³⁺-6-AMINO- (1H)-1, 4, 8, 11-tetraazacyclotridecane-5, 7-dione chelate: A bifunctional chelator as positron emission tomography tracers

The interaction of metal ions with biomolecules and effect of coordination geometry of chelate as imaging agent can be a prudent aspect in developing probes for diagnostics. Metal complexes are widely used in all the imaging modalities. Thus in molecular diagnostics, molecular modeling plays an important role for design and analysis of structural, electronic parameters, metal–ligand complex structure, ligand selectivity, coordination number, lipophilicity, and thermodynamic stability. We have done molecular modeling studies of proposed bifunctional chelate (BFCs), 6-Amino- (1H)-1,4,8,11- tetraazacyclotridecane-5,7-dione, with metals namely M²⁺; Cu-64/M³⁺; Ga-68 that holds great potential for the development of molecular probes for PET. The methodology includes DFT analysis of ligands and transition metal complexes at ground state spin systems in vacuum and in solvent phase by Poisson Boltzmann Finite element method. Docking evaluation identifies binding metal-chelate complex with antibody which is an important aspect in case of site specific targeted therapeutic radiopharmaceuticals. Geometric parameters for ligand were comparable with X-ray crystallographic structure in methanol. With the diagnosed Cu (II) and Ga (III) chelates, fundamental properties such as cavity size alone with proper denticity were observed to obtain thermochemical parameters. In case of Ga (III), due to similarity of ionic radii with high spin Fe (III) in-vivo, complexation properties with Fe (III) were also determined. The comparative studies resulted in modeling different possible spin orientations. The effect of different atomic orientations on energy and other electronic properties of the system were calculated. Also studied parameters include spin density and its distribution, nature of singly occupied molecular orbitals and symmetry-unrestrained optimization. Accurate spin density distributions are obtained by modification of the nuclear charge on metal ions. Interactions of these metals-chelates as molecular docking stations in imaging with antibodies were evaluated with and without metal loaded chelate. In this molecular modeling techniques are valuable in understanding behaviour and nature of Cu-64 and Ga-68 based BFCs when conjugated to peptide or monoclonal antibody for receptor of interest. Hence, theoretical studies play important role in the development of molecular imaging agents based on radiometal-BFC that requires evasion to excessive radiation damage to non-target cells under physiological conditions. (author)