Synthesis and characterization of an MRI Gd-based probe designed to target the translocator protein

DPA‐713 is the lead compound of a recently reported pyrazolo[1,5‐a]pyrimidineacetamide series, targeting the translocator protein (TSPO 18 kDa), and as such, this structure, as well as closely related derivatives, have been already successfully used as positron emission tomography radioligands. On the basis of the pharmacological core of this ligands series, a new magnetic resonance imaging probe, coded DPA‐C6‐(Gd)DOTAMA was designed and successfully synthesized in six steps and 13% overall yield from DPA‐713. The Gd‐DOTA monoamide cage (DOTA = 1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid) represents the magnetic resonance imaging reporter, which is spaced from the phenylpyrazolo[1,5‐a]pyrimidineacetamide moiety (DPA‐713 motif) by a six carbon‐atom chain. DPA‐C6‐(Gd)DOTAMA relaxometric characterization showed the typical behavior of a small‐sized molecule (relaxivity value: 6.02 mM−1 s−1 at 20 MHz). The good hydrophilicity of the metal chelate makes DPA‐C6‐(Gd)DOTAMA soluble in water, affecting thus its biodistribution with respect to the parent lipophilic DPA‐713 molecule. For this reason, it was deemed of interest to load the probe to a large carrier in order to increase its residence lifetime in blood. Whereas DPA‐C6‐(Gd)DOTAMA binds to serum albumin with a low affinity constant, it can be entrapped into liposomes (both in the membrane and in the inner aqueous cavity). The stability of the supramolecular adduct formed by the Gd‐complex and liposomes was assessed by a competition test with albumin. Copyright © 2013 John Wiley & Sons, Ltd. A new derivative of the pyrazolo[1,5‐a]pyrimidineacetamide DPA‐713 (a molecule that is known to target the translocator protein (TSPO 18 kDa)) bearing a Gd‐DOTA monoamide cage has been designed, synthesized and its relaxometric properties evaluated. Its interaction with human serum albumin and its entrapment in selected liposomes have been explored in order to improve its properties as magnetic resonance imaging targeting agent.