Diphosphine Bioconjugates via Pt(0)-Catalyzed Hydrophosphination. A Versatile Chelator Platform for Technetium-99m and Rhenium-188 Radiolabeling of Biomolecules.

The ability to append targeting biomolecules to chelators that efficiently coordinate to the diagnostic imaging radionuclide, 99m Tc, and the therapeutic radionuclide, 188 Re, can potentially enable receptor-targeted "theranostic" treatment of disease. Here we show that Pt(0)-catalyzed hydrophosphination reactions are well-suited to the derivatization of diphosphines with biomolecular moieties enabling the efficient synthesis of ligands of the type Ph 2 PCH 2 CH 2 P(CH 2 CH 2 -Glc) 2 ( L , where Glc = a glucose moiety) using the readily accessible Ph 2 PCH 2 CH 2 PH 2 and acryl derivatives. It is shown that hydrophosphination of an acrylate derivative of a deprotected glucose can be carried out in aqueous media. Furthermore, the resulting glucose-chelator conjugates can be radiolabeled with either 99m Tc(V) or 188 Re(V) in high radiochemical yields (>95%), to furnish separable mixtures of cis - and trans -[M(O) 2 L 2 ] + (M = Tc, Re). Single photon emission computed tomography (SPECT) imaging and ex vivo biodistribution in healthy mice show that each isomer possesses favorable pharmacokinetic properties, with rapid clearance from blood circulation via a renal pathway. Both cis -[ 99m Tc(O) 2 L 2 ] + and trans -[ 99m Tc(O) 2 L 2 ] + exhibit high stability in serum. This new class of functionalized diphosphine chelators has the potential to provide access to receptor-targeted dual diagnostic/therapeutic pairs of radiopharmaceutical agents, for molecular 99m Tc SPECT imaging and 188 Re systemic radiotherapy.