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Controlled axial coordination: solid-phase synthesis and purification of metallo-radiopharmaceuticals.

Solid-supported reagents show great potential for improving the synthesis of radiodiagnostic agents, in terms of radiochemical yield and purity, as well as convenience and safety. The preparation of the positron emission tomography (PET) imaging agent [F]-2-fluoro-2-deoxy-d-glucose has recently been demonstrated using a solid-bound substrate which is selectively cleaved from the solid support upon reaction with [F]-fluoride ions. Whilst this covalent approach is appropriate for the nucleophilic substitution chemistry of fluoride ions, its utility with metallonuclides is limited and the only examples to date have used Tc in conjunction with proligands attached to resins and gold surfaces. Conventional solid-phase synthesis is therefore limited by the requirement for proligands possessing a donor group which can both be covalently attached to the solid support and cleaved from it upon coordination to the desired metal ion. Herein, we report a novel strategy for solid-phase synthesis based on selective axial coordination of Zn substrates to 4-(dimethylamino)pyridine(DMAP)-functionalized polystyrene resin and exemplify its use in the preparation and purification of known and potential Cu and Tc radiopharmaceuticals. This strategy is applicable to a wide range of metallic radionuclides and is suitable for the macrocyclic ligand systems that are favored in nuclear medicine because of their high in vivo stability. Zn complexes of tetradentate ligands that are constrained in pseudo-square-planar conformations can potentially bind a fifth donor atom in an axial coordination site. Jahn–Teller distortion disfavors the coordination of a fifth donor atom in the axial site of analogous Cu complexes. A Zn precursor can be bound to polymer-supported DMAP by axial coordination. Upon transmetalation of the Zn complex with Cu, the coordinate bond to the solid support is broken and only the transmetalated complex is released from the resin (Scheme 1 a). Similarly, polystyrene-supported DMAP can be used to selectively bind the Zn complex from a solution-phase reaction mixture leaving only the radiolabeled complex in solution (Scheme 1b).