Measurements of kinetic stability, blood-brain barrier permeability and cytotoxicity for two thulium based contrast agents

Successful translation of smart contrast agents (SCAs) from the benchtop into biological use depends on several key intermediate steps. The measurement of ex vivo kinetic inertness, in vivo blood-brain barrier permeability and in vivo cytotoxicity are three important steps in assessing the feasibility of using any SCA for any ulterior biological studies. Over the past decade, a new non-invasive method for simultaneous measurements of temperature and pH was developed, based on the strong dependence on temperature and pH of the proton chemical shifts from the complex between the thulium ion and the macrocyclic chelate 1,4,7,10- tetraazacyclododecane-N,N’,N’’,N’’’-tetra (methylene phosphonate) or TmDOTP5-. Thanks to the high sensitivity of each resonance on temperature and pH, models can be developed to determine both temperature and pH simultaneously and very accurately in the rat brain [4]. More recently, a new temperature probe was introduced, also relying on thulium as paramagnetic ion, but for which the macrocyclic chelate is 1,4,7,10-tetraazacyclododecane-1,4,7,10- tetramethyl-1,4,7,10-tetraacetate or TmDOTMA-. The methyl 1H chemical shift of TmDOTMA- is pH-independent. In the present work, we measured ex vivo kinetic inertness, in vivo blood-brain barrier permeability and in vivo cytotoxicity of TmDOTP5- and TmDOTMA- agents.