Aqueous syntheses of [(Cp-R)M(CO) 3] type complexes (Cp = cyclopentadienyl, M = Mn, 99mTc, Re) with bioactive functionalities

Abstract

We describe reactions of [ 99mTc(H 2O) 3(CO) 3)] + ( 1) with Diels–Alder products of cyclopentadiene such as “Thiele’s acid” (HCp-COOH) 2 ( 2) and derivatives thereof in which the corresponding [(Cp-COOH) 99mTc(CO) 3)] ( 3) complex did form in water. We propose a metal mediated Diels–Alder reaction mechanism. To show that this reaction was not limited to carboxylate groups, we synthesized conjugates of 2 (HCp-CONHR) 2 ( 4a–c) ( 4a, R = benzyl amine; 4b, R = N α-Boc- l-2,3-diaminopropionic acid and 4c, R = glycine). The corresponding 99mTc complexes [( 4a) 99mTc(CO) 3)] 6a, [( 4b) 99mTc(CO) 3)] 6b and [( 4c) 99mTc(CO) 3)] 6c have been prepared along the same route as for Thiele’s acid in aqueous media demonstrating the general applicability of this synthetic strategy. The authenticity of the 99mTc complexes on the no carrier added level have been confirmed by chromatographic comparison with the structurally characterized manganese or rhenium complexes. Studies of the reaction of 1 with Thiele’s acid bound to a solid phase resin demonstrated the formation of [(Cp-COOH) 99mTc(CO) 3)] 3 in a heterogeneous reaction. This is the first evidence for the formation of no carrier added 99mTc radiopharmaceuticals containing cyclopentadienyl ligands via solid phase syntheses. Macroscopically, the manganese analogue 5a and the rhenium complexes 5b–c have been prepared and characterized by IR, NMR, ESI-MS and X-ray crystallography for 5a (monoclinic, P2 1/ c, a = 9.8696(2) Å, b = 25.8533(4) Å, c = 11.8414(2) Å, β = 98.7322(17)°) in order to unambiguously assign the authenticity of the corresponding 99mTc complexes.