Synthesis and Characterization of Nonsteroidal-Linked M(CO)3+(M = 99mTc, Re) Compounds Based on the Androgen Receptor Targeting Molecule Flutamide

Androgen receptors are overexpressed in most primary and metastatic prostate cancers. A series of single photon emission computed tomography imaging agents (SPECT) utilizing the organometallic radioactive imaging species, fac-99mTc(OH(2))(3)(CO)(3)+, were prepared on the basis of the structure of Flutamide, a potent nonsteroidal antiandrogen prostate cancer drug. Novel bifunctional chelate-linked Flutamide analogues were prepared using a newly developed universal alkylating reagent, 2-bromo-N-[4-nitro-3-(trifluoromethyl)phenyl]-acetamide, 1. From compound 1, several ligands (i.e., cysteine 2, histidine 5, imidazole 3) were conjugated to the flutamide derivative to yield targeting ligands capable of either tridentate or monodentate coordination in a "2 + 1" complex. fac-Re(CO)(3)+ complexes were prepared and characterized with the functionalized conjugates to yield fac-Re(CO)(3)(2-amino-3-(1-(2-(4-nitro-3-(trifluoromethyl)phenylamino)-2-oxoethyl)-1H-imidazol-4-yl) propanoate), 4, fac-Re (CO)(3)(2-(S-cysteinyl)-N-[4-nitro-3-(trifluoromethyl) phenyl]-acetamide), 6, and fac-Re(CO)(3)(picolinate)(2-(1H-imidazol-1-yl)-N-[4-nitro-3-(trifluoromethyl)phenyl]-acetamide), 7. The corresponding radioactive 99mTc analogues were prepared and stability studies of the radioactive compounds were also conducted.