Noninvasive medical imaging techniques such as single-photon emission computed tomography (SPECT) or positron emission tomography (PET), are valuable tools for the development and validation of new therapeutic molecules. That approach requires the conjugation of a radioactive source emitting either y-rays or positrons with a biological tracer (e.g. DOTATOC). Among the potentially useful radionuclides available, 111In3+ (SPECT), 64Cu2+, and 68Ga3+ (PET) have attracted increasing attention over the last years for medical applications. To minimize the in vivo release of the radioactive cation by transmetalation or transchelation with biological ligands, it is essential to trap selectively the targeted radiometal by a suitable bifunctional chelator that forms stable and inert complexes. Many studies involving linear or cyclic sequestering agents have been reported, but their choice has only rarely been supported by a thorough structural, thermodynamic, and kinetic characterization of their coordination properties. The purpose of our work is to assess the structural and thermodynamic consequences of replacing an acetate binding unit by an amide group that mimics the peptide bond found in the linker of DOTATOC-like radiopharmaceuticals. Complexes incorporating 12, 13, or 14-membered N-functionalized tetraazamacrocycles and the targeted cations (Cu2+, Ga3+, In3+) have been isolated and structurally characterized by X-ray diffraction and various spectroscopic methods (NMR, EPR, UV-vis, IR, ESI-MS). Solution equilibrium studies with a range of cations including some biologically important ones (Cu2+, Ga3+, In3+, Mg2+, Ca2+, Fe3+, Zn2+) will also been presented, together with electrochemical measurements on some copper(II) complexes which are not likely to be reduced under physiological conditions by biological reducing agents.
