PH-controlled coordination mode rearrangements of "clickable" Huisgen-based multidentate ligands with [M^I(CO)₃] ⁺ (M = Re, ^99mTc)

The viability of the Huisgen cycloaddition reaction for clickable radiopharmaceutical probes was explored with an alkyne-functionalized 2-[(pyridin-2-ylmethyl)amino]acetic acid (PMAA) ligand system, 3, and fac-[M^I(OH₂)₃(CO)₃]⁺ (M = Re, ^99mTc). Two synthetic strategies, (1) click, then chelate and (2) chelate, then click, were investigated to determine the impact of assembly order on the reactivity of the system. In the click, then chelate approach, fac-[M^I(OH₂)₃(CO)₃]⁺ was reacted with the PMAA ligand "clicked" to the benzyl azide, 5, to yield two unique coordination species, fac-[M^I(CO) ₃(O,N_amine,N_py-5)], M = Re (8), ^99mTc (8A), and fac-[M^I(CO)₃(N _tri,N_amine,N_py-5)], M = Re (9), ^99mTc (9A), where coordination is through the triazole (N _tri), central amine (N_amine), pyridine (N_py), or carboxylate (O). Depending on the reaction pH, different ratios of complexes 8(A) and 9(A) were observed, but single species were obtained of (O,N _amine,N_py) coordination, 8(A), in basic pHs (>9) and (N_tri,N_amine,N_py) coordination, 9(A), in slightly acidic pHs (<4). In the chelate, then click approach, the (O,N _amine,N_py) coordination of [M^I(CO) ₃]⁺ was preorganized in the alkyne-functionalized fac-[M^I(CO)₃(O,N_amine,N_py-3)], M = Re (6), ^99mTc (6A), followed by standard Cu^I-catalyzed Huisgen "click" conditions at pH ≈ 7.4, where the (O,N _amine,N_py) coordination mode remained unchanged upon formation of the triazole product in the clicked molecule. Despite the slow substitution kinetics of the low-spin d⁶ metal, the coordination modes (O,N_amine,N_py) and (N_tri,N _amine,N_py) were found to reversibly intraconvert between 8(A) and 9(A) based upon changes in pH that mirrored the (O,N _amine,N_py) coordination in basic pHs and (N _tri,N_amine,N_py) coordination in acidic pHs. Comparison of the Re and ^99mTc analogs also revealed faster intraconversion between the coordination modes for ^99mTc.