Diphosphine Bioconjugates via Pt(0)-Catalyzed Hydrophosphination. A Versatile Chelator Platform for Technetium-99m...

The ability to append targeting biomolecules to chelators that efficiently coordinate to the diagnostic imaging radionuclide, ^99mTc, and the therapeutic radionuclide, ¹⁸⁸Re, 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 Ph₂PCH₂CH₂P(CH₂CH₂-Glc)₂ (L, where Glc = a glucose moiety) using the readily accessible Ph₂PCH₂CH₂PH₂ 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 ^99mTc(V) or ¹⁸⁸Re(V) in high radiochemical yields (>95%), to furnish separable mixtures of cis- and trans-[M(O)₂L₂]⁺ (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-[^99mTc(O)₂L₂]⁺ and trans-[^99mTc(O)₂L₂]⁺ 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 ^99mTc SPECT imaging and ¹⁸⁸Re systemic radiotherapy.