pH-Controlled Coordination Mode Rearrangements of “Clickable” Huisgen-Based Multidentate Ligands with [M^I(CO)₃]⁺ (M = Re, ^99mTc)

Abstract

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, (99m)Tc). 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), (99m)Tc (8A), and fac-[M(I)(CO)3(N(tri),N(amine),N(py)-5)], M = Re (9), (99m)Tc (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), (99m)Tc (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 d(6) 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 (99m)Tc analogs also revealed faster intraconversion between the coordination modes for (99m)Tc.

Cu-Free 1,3-Dipolar Cycloaddition Click Reactions To Form Isoxazole Linkers in Chelating Ligands for fac-[MI(CO)3]+ Centers (M = Re, 99mTc)

“…An increased reactivity in CuAAC reactions performed with 10 and 11 was proposed because of the presence of fac -[M I (CO) 3 ] + ; similar effects due to the metal center may also impact the isoxazole reaction. 12,17 In both cycloaddition reactions with 4 in the present study, the corresponding Re complexes ( 8 and 9 ) were formed in moderate-to-good yields after isolation. Analytical characterization data of 8 and 9 prepared by the chelate, then click approach from 10 and 11 corresponded to the data obtained via the click, then chelate method from 5 and 7 , showing that both strategies successfully produced the final Re complexes.…”

“…26 Re bond distances (Å) and angles (deg) are analogous to those of previously reported complexes with this chelate (Table S1 in the Supporting Information, SI). 12 The structure clearly confirms noncoordination of the isoxazole linker with the Re center. IR analysis gave the expected CO peaks for fac -[Re I (CO) 3 ] + complexes 12,17 and showed a shift in the IR of the isoxazole ring peak (from 1620 cm –1 in 5 to 1611 cm –1 in 8 and from 1620 cm –1 in 7 to 1609 cm –1 in 9 ).…”

“…8,12−18 While our group has demonstrated the potency of the CuAAC reaction to couple fac -[M I (CO) 3 ] + complexes under mild conditions (15 min, 37 °C) using 1,2,3-triazole as a linker between the metal and targeting vector, uncoordinated 1,2,3-triazole can impact the coordination mode and stability of the complex. 12,17 …”

“…The three different CH 2 ’s exhibited AB quartet splitting patterns, indicating a unique magnetic environment for each proton as expected because of the asymmetric nature of the chelate. 12 The ambiguity of the NMR splitting patterns does not clearly elucidate the coordination environment of the metal center; consequently, X-ray crystallography was used to determine the structure. Single crystals of 9 were grown by slow evaporation of a dichloromethane/methanol (2:1) mixture for X-ray diffraction analysis (Figure 1).…”

Solvent effects on the photophysical properties of Bu4N[(4,4′-bpy)Re(CO)3(bpy-5,5′-diCOO)] complex. A combined experimental and computational study

“…A major drawback, however, relies on their limited solubility in aqueous media. In fact, most of the fac-ReX(CO) 3 (α-diimine) complexes which annually appear on the literature reports are exclusively soluble in organic solvents while only a few of them can be managed in aqueous solutions at physiological pHs [14][15][16][17][18][19][20][21]. In previous work we have synthesized and characterized a water soluble fac-ReX(CO) 3 (α-diimine) complex coordinating the ligands 2,2′-bipyridine-5,5′-dicarboxylate (bpy-5,5′-diCOO) and 4,4′-bipyridine (4,4′-bpy) [22].…”