Synthesis of 17-alpha-substituted estradiol-pyridin-2-yl hydrazine conjugates as effective ligands for labeling with Alberto's complex fac-[Re(OH2)3(CO)3]+ in water.

The development of (99m)Tc-estradiol radiopharmaceuticals would be advantageous for the detection of estrogen receptor-positive breast tumors. Estradiol derivatives conjugated to organometallic tricarbonyl-Tc(I) and related Re(I) complexes are capable of achieving high receptor binding affinity, but effective methods for synthesizing radiolabeled complexes in water are not available. Our interest in the synthesis of 2-hydrazinopyridines as ligands for Tc and Re led us to investigate Pd-catalyzed amination reactions of halo-pyridine substrates with di-tert-butyl hydrazodiformate. Both 2- and 4-substituted halo-pyridine substrates undergo C-N coupling with di-tert-butyl hydrazodiformate to produce Boc-protected pyridine hydrazine derivatives. Only highly electrophilic 3-pyridine halides were converted to the hydrazine. The Boc-protected 5-bromopyridin-2-yl hydrazine substrate 3 was prepared by regioselective substitution at the 2-position of 2,5-dibromopyridine. This bifunctional chelate was attached to ethynyl or vinyl groups at the 17alpha position of estradiol, using Sonogashira and Suzuki/Miyaura coupling reactions to synthesize 1 and 2 in high yields, respectively. Deprotection of 1 under acidic conditions provided the hydrazine hydrochloride salt 25. The 17alpha-estradiol-tricarbonylrhenium(I) complex 4 was synthesized by labeling 25 with fac-[Re(OH(2))(3)(CO)(3)](+) in aqueous ethanol. This complex exhibited excellent stability and high receptor binding affinity for the estrogen receptor, and it is a promising model for evaluation of the analogous Tc-99m complexes as diagnostic imaging agents for breast tumors.