The complexes between gamma-cyclodextrin and lanthanide (111) chelates of the polyazamacrocycles DOTA (DOTA equivalent to 1,4,7,10-tertraazacyclododecane-1,4,7,10-tetraacetate) and DOTP (DOTP equivalent to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylenephosphonate) have been thought out to enhance the potential of such chelates as contrast agents for MRI. Given the actual demand for the design of new contrast agents, we thought it worthwhile to confirm previous results for the equilibrium constant K obtained by one of us by NMR on the DOTP complex, as well as to determine K for a new one with DOTA. Further, we wanted to study and quantify the interactions present in these complexes, with a view to improve them in newly designed complexes.The interactions between gamma-cyclodextrin and the lanthanide (III)-polyazamacrocyclic chelates, [Tm(DOTP)](5-), and [Gd(DOTA)](-) were then studied by isothermal calorimetry (ITC) and molecular dynamics. The calorimetric experiments can be interpreted by considering that in both cases there is a weak association, characterized by low values for the equilibrium constant as well as for the molar enthalpy change for complex formation, at T = 298.15 K. The K value for the complex with DOTP obtained now by ITC is of the same order of magnitude of the one determined previously by NMR. Further, the complex formation seems rather insensitive to the macrocycle, as the values now obtained by ITC for the DOTA complex are very similar to the ones obtained for the DOTP complex.We have also carried out molecular dynamics simulations on these very same inclusion complexes, which provided quantitative data on the interactions present, as well as a plausible explanation for the data obtained, leading to the proposal of possible solutions to improve the modelling of new contrast agents on a host-guest basis. (C) 2003 Elsevier Ltd. All rights reserved.