A pyrazolylamine‐phosphonate monoester chelator for the fac ‐[M(CO) 3 ] + core (M = Re, 99m Tc): synthesis, coordination properties and biological assessment

Aiming to develop new strategies for the labeling of hydroxyl‐containing biomolecules with the organometallic core fac ‐[ 99m Tc(CO) 3 ] + , we have prepared a new model bifunctional chelator, L4 (ethyl hydrogen (2‐{[2‐(3,5‐dimethyl‐1 H ‐pyrazol‐1‐yl)ethyl]amino}ethyl)phosphonate), combining a pyrazolyl‐amine chelating group and a monophosphonate ethyl ester function (–P(O)OHOEt). The phosphonate group allows metal stabilization, and, simultaneously, can be considered as a potential attachment site for a biomolecule. Reaction of L4 with the precursor [ 99m Tc(H 2 O) 3 (CO) 3 ] + gave the model radiocomplex [ 99m Tc(CO) 3 (k 3 ‐L4)] ( 6a ). This radiocomplex was identified by comparing its chromatographic profile with that of the corresponding Re analog ( 6 ) under the same conditions, also prepared and fully characterized by the usual analytical techniques. Radiocomplex 6a is moderately lipophilic (log P o/w = 1.07), presenting high stability in vitro without any measurable decomposition or ligand exchange, even in the presence of strong competing chelators such as histidine and cysteine (37°C, 24 h). Biodistribution studies of the complex in CD‐1 mice indicated a rapid blood clearance, and a rapid clearance from main organs, occurring primarily through the hepatobiliary pathway. Complex 6a presents also a high robustness in vivo , demonstrated by its resistance to metabolic degradation in blood, and intact excretion into the urine, after RP‐HPLC analysis of blood and urine samples. Copyright © 2007 John Wiley & Sons, Ltd.