The synthesis and biological evaluation of integrated and conjugated Re/Tc-99m-containing '3+1' and cyclopentadienyltricarbonyl (CPTM) estrogen complexes as receptor-based imaging agents for breast cancer.

摘要

In our ongoing effort to produce technetium-labeled estrogen radiopharmaceuticals to be used as receptor-based imaging agents for hormone-dependent breast cancer tumors, we have synthesized a number of rhenium and technetium complexes based on the integrated and conjugated designs.; The integrated complexes take advantage of the “3+1” chelate approach to incorporating the rhenium. metal, where a tridentate ligand and monodentate ligand surround an oxorhenium core. These oxorhenium chelates (36, 37) were designed to mimic either estradiol (1), or tetrahydrochrysene (THC) (37). The monodentate component of estradiol mimic 36 is a p-hydroxyphenethyl thiol ligand substituted at the benzylic and homobenzylic positions with ethyl substituents. While model complexes 38 and 39 of this estradiol mimic were easily made, steric hindrance of the secondary thiol prevented the formation of the target complex with the disubstituted ligand. THC mimics 37a–c utilize a unique bis(thiomethyl)pyridine as the tridentate ligand, and are the first of their kind to be made. While these THC mimics display interesting VT-NMR behavior and reasonable lipophilicities, their binding affinities to the estrogen receptor were rather low.; The conjugated complexes herein involve estradiol substituted at the 7α position with rhenium and technetium complexes based on the “3+1” and cyclopentadienyltricarbonyl designs. The first set of complexes utilize a hexyl tether to bridge the metal-containing moiety to the 7α position of estradiol. The highest binding affinity for this series of complexes was observed with a “3+1” complex bearing an bis(2-mercaptoethyl)methyl amine as the tridentate ligand (66, 45%) and a CpTR complex employing an amide linkage (67b, 24%). Studies showed that the Tc analogs were too lipophilic for in vivo use, so we pursued the synthesis of CpTR amides containing ether functionalities in the 7α side-chain. This led to two new complexes: short-chain monoether complex 88, and long-chain polyether complex 87. Both retained good binding affinity, and both were more polar to some extent. However, tissue distribution studies of the Tc analogs showed no significant change from the original amide 67b, although uptake in many non-target organs was lower.