Chelate complexes of rhenium and technetium: toward their potential applications as radiopharmaceuticals

Technetium-99m is the major isotope used in diagnostic radiopharmaceuticals, and it will continue to dominate in the future. Macroscopic studies of stable technetium-99 complexes are very important in searching for new diagnostic radiopharmaceuticals based on known structural information. Possessing similar chemistry but being non-radioactive, rhenium is a good model for technetium. In addition, two isotopes of this element: rhenium-186 and rhenium-188, are good potential radionuclides for therapeutic radiopharmaceuticals. Therefore, complexes of both metals were synthesized with naturally occurring or easily synthesized chelates, and with new ligands designed to stabilize both metals in intermediate oxidation states. Technetium(V) and rhenium(V) complexes of the form [MOXL₂] and [MOX₃(ma)]-, where L is a bidentate (0,0) monoprotic ligand, 2-methyl-3-oxy-4-pyronate (maltolate, ma") or l,2-dimethyl-3-oxy-4-pyridinonate (dpp-) and X is a halo ligand, X = CI (M = Tc) or Br (M = Re), have been synthesized by ligand substitution reactions on [TcOCl₄]⁻ or [ReOBr₄- anions. The structures of [ReOBr(ma)₂], [(n-Bu)₄N][ReOBr₃(ma)] and [(n-Bu)₄N][TcOCl₃(ma)] were determined by X-ray crystallography. Conversion of [Re0Br₃(ma)]⁻ to [ReOBr(ma)₂] was achieved by addition of excess Hma or standing. The rhenium(V) and technetium (V) complexes: [ReO(apa)], [{ReO(epa)}₂0], and [TcOCl(epa)] from a potentially pentadentate (N₃O₂) ligand precursor, N,N'-3-azapentane-l,5- diylbis(3-(l-iminoethyl)-6-methyl-2H-pyran-2,4(3H)-dione) (H3apa), or a potentially tetradentate (N₂O₂) ligand precursor, N,N'-ethylene-diylbis(3-(l-iniinoethyl)-6-methyl-2i7- pyran-2,4(3if)-dione) (H2erpa) are described. There was evidence indicating that H2ppa, N,N'- propylene-diylbis(3-(l-iminoethyl)-6-methyl-2H-pyran-2,4(3H)-dione), hydrolyzed in the course of coordination, forming a rhenium complex of the bidentate monoprotic (0,0) dehydroacetate. A modified preparation of the hydrochloride salt of a potentially tridentate ligand precursor, bis(o-hydroxyphenyl)phenylphosphine (abbreviated H₂PO₂HCI) is described. From H₂PO₂HCI, and a potentially bidentate analog, o-hydroxyphenyldiphenylphosphine (HPO), POxx⁻ (x = 1,2) complexes of rhenium(V) and technetium(V) were prepared by metathesis reactions with the appropriate metal(V) precursors, and/or by reduction/coordination reactions with ammonium perrhenate or pertechnetate. The new POx complexes fall into four categories: bis(PO) complexes [(MOCl(PO)]₂ (M = Re or Tc), and [ReN(PO)₂(PPh₃)]; mono(P0₂) complexes [ReZCl(PPh₃)(P0₂)] ( Z = O or NPh); mixed(PO/PO₂) complexes [ReZ(PO)(P0₂)] (Z= O or NPh); and mixed(P0₂HP0₂) complexes [MO(P02)(HPC>2)] (M = Re or Tc). Geometrical isomerism was observed for several complexes. The structures of fac-cis-(P,P)- [Re(NPh)Cl(PPh3)(P02)] and/ac-cw-(P,P)-[ReO(PO)(P02)] have been solved by X-ray crystallography. Preparation of the hydrochloride salt of a new potentially hexadentate ligand precursor P,P,P',P'-tetrakis(o-hydroxyphenyl)diphosphinoethane (abbreviated H₄P₂O₄2HCI) is described. From H₄P₂O₄2HCI, two dinuclear complexes, [Re₂O₂Cl₂(PPh₃)₂(μ-P₂0₄)], and [(n - Bu)₄N]₂[Re₂0₂Br₄(μ-P₂0₄)], and two mononuclear complexes, [M(HP₂O₄)] nS (M = Tc, nS = 2EtOH0.5PhMe; M = Fe, nS = 2H₂O), were synthesized. The Tc complex was synthesized rapidly by a reduction/coordination route from the reaction of ammonium pertechnetate with H₄P₂O₄2HCI, in which the functionalized phosphine is a reducing as well as a ligating agent. Cyclic voltammetric study of the complex [Tc(HP₂O₄)]-2EtOH0.5PhMe revealed that the Tc(III) complex is well stabilized by the coordination environment. Labeling H₂P0₂ HCl and H₄P₂O₄2HCI with ⁹⁹mc was also pursued. The TLC results suggested that both ligands are labeled easily and rapidly in EtOH, in high radiochemical yield. The ⁹⁹mTc labeled complexes were found to be hydrolytically stable. The labeling procedures, without an added reducing agent, are simple and kit-amenable for potential clinical application. Two isomers are present in [⁹⁹mTc(P0₂)(HP0₂)], consistent with the macroscopic chemistry. The preliminary in vivo biodistribution studies of the radiolabeled [⁹⁹m Tc(HP₂)₄)] complex in mice showed that the complex has high liver affinity, and is worthy of further investigation into its use as a potential liver function agent.

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