One-step, kit-based radiopharmaceuticals for molecular SPECT imaging: a versatile diphosphine chelator for (99m)Tc radiolabelling of peptides

Radiotracers labelled with technetium-99m ((99m)Tc) enable accessible diagnostic imaging of disease, provided that radiotracer preparation is simple. Whilst (99m)Tc radiopharmaceuticals for imaging perfusion are routinely prepared from kits, and regularly used in healthcare, there are no (99m)Tc-labelled receptor-targeted radiopharmaceuticals in widespread clinical use. This is in part due to the multistep radiosyntheses required for the latter. We demonstrate that the diphosphine, 2,3-bis(diphenylphosphino)maleic anhydride (BMA), is an excellent platform for preparation of kit-based, receptor-targeted (99m)Tc-labelled radiotracers: its conjugates are simple to prepare and can be easily labelled with (99m)Tc using one-step, kit-based protocols. Here, reaction of BMA with the α(v)β(3)-integrin receptor targeted cyclic peptide, Arg-Gly-Asp-DPhe-Lys (RGD), provided the first diphosphine-peptide conjugate, DP-RGD. DP-RGD was incorporated into a “kit”, and addition of a saline solution containing (99m)TcO(4)(−) to this kit, followed by heating, furnished the radiotracer [(99m)TcO(2)(DP-RGD)(2)](+) in consistently high radiochemical yields (>90%). The analogous [ReO(2)(DP-RGD)(2)](+) compound was prepared and characterised, revealing that both [(99m)TcO(2)(DP-RGD)(2)](+) and [ReO(2)(DP-RGD)(2)](+) consist of a mixture of cis and trans geometric isomers. Finally, [(99m)TcO(2)(DP-RGD)(2)](+) exhibited high metabolic stability, and selectively targeted α(v)β(3)-integrin receptors, enabling in vivo SPECT imaging of α(v)β(3)-integrin receptor expression in mice.