From symmetrical to asymmetrical nitrido phosphino-thiol complexes: a new class of neutral mixed-ligand (99m)Tc compounds as potential brain imaging agents.

A general procedure is presented for the preparation of a new class of nitrido asymmetrical Tc-99m complexes containing two different bidentate ligands bound to the same [Tc(N)]2+ core that could be used to design either essential or target specific imaging agents. This procedure is based on the chemical properties of a new monosubstituted [Tc(N)(R2PS)Cl(PPh3)] species composed of a TcN multiple bond and an ancillary phosphine thiol ligand (R2PSH). This intermediate readily reacts with bidentate mononegative ligands (S--Y) containing soft pi-donor coordinating atoms to give neutral pentacoordinate asymmetrical complexes of the type [Tc(N)(R2PS)(S--Y)]. The ability of several bidentate ligands containing different combination of heteroatoms (S, N, O) to form complexes with the [Tc(N)(R2PS)]+ building block was investigated. It was found that mononegative dithiocarbamate (DTC) or cysteine carboxyl derivate ligands promptly react with the monosubstituted species to form the final mixed compound in high yield. Preliminary biodistribution data in rats of some representative [Tc(N)(R2PS)(DTC)] compounds revealed an interesting initial brain uptake (in the range 0.20 +/- 0.01% ID/g and 0.91 +/- 0.06% ID/g), indicating their ability to cross in and out of the intact BBB. In these complexes the dithiocarbamate, or more generally the bidentate ligand (S--Y), can be designed to carry a functional group or a bioactive molecule, which could be involved in a trapping mechanism to increase brain retention for longer time intervals. These results could be conveniently utilized to devise a new procedure for the production of a novel class of brain perfusion and/or brain receptor imaging agents.

Synthesis of a Novel Class of Trigonal Bipyramidal Nitrido Tc(V) Complexes with Phosphino-Thiol Ligands. Crystal Structure of [(99g)Tc(N)(L(1))(2)] [L(1) = 2-(Diphenylphosphino)ethanethiolato] and [(99g)Tc(N)(L(5))(2)] [L(5) = 2-(Ditolylphosphino)propanethiolato].

Reactions of the precursor complexes [(99g)Tc(N)Cl(2)(PPh(3))(2)] and [(99g)Tc(N)Cl(4)](-) with phosphine-thiol ligands (HL(n)()) of the type R(2)PCH(2)CH(2)SH (R = phenyl, methoxypropyl), R(2)'PCH(2)CH(2)CH(2)SH (R' = phenyl, tolyl), and R(2)' 'P-o-C(6)H(4)SH (R' ' = phenyl) afforded the five-coordinated, disubstituted nitrido technetium(V) complexes [(99g)Tc(N)(L(n)())(2)]. The complexes were characterized by elemental analysis, (1)H and (31)P NMR spectroscopy, FT IR, and positive FAB MS spectra. Structural characterization of [(99g)Tc(N)(L(1))(2)] (1) [HL(1) = (C(6)H(5))(2)PCH(2)CH(2)SH] and [(99g)Tc(N)(L(5))(2)] (5) [HL(5) = (o-CH(3)C(6)H(4))(2)PCH(2)CH(2)CH(2)SH] showed that the bidentate phosphino-thiol ligands are coordinated to the technetium center through the neutral phosphorus atom and the deprotonated thiol sulfur atom. These complexes possess an uncommon trigonal bipyramidal geometry with the two phosphorus atoms occupying the two transaxial positions and the two sulfur atoms on the equatorial plane along with the nitrido nitrogen atom. Compound 1 crystallizes in the monoclinic space group C2/c, a = 24.84(2) Å, b = 7.327(6) Å, c = 31.52(2) Å, beta = 111.06(10) degrees, and Z = 8. Compound 5 crystallizes in the monoclinic space group P2(1)/n, a = 11.090(1) Å, b = 14.387(2) Å, c = 11.087(1) Å, beta = 113.62(1) degrees, and Z = 2.