Synthesis of 17-α-Substituted Estradiol-Pyridin-2-yl Hydrazine Conjugates as Effective Ligands for Labeling with Alberto's Complex <i>f</i><i>ac</i>-[Re(OH<sub>2</sub>)<sub>3</sub>(CO)<sub>3</sub>]<sup>+</sup> in Water

The development of <sup>99m</sup>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-<i>tert</i>-butyl hydrazodiformate. Both 2- and 4-substituted halo-pyridine substrates undergo C−N coupling with di-<i>tert</i>-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 <b>3</b> 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 17α position of estradiol, using Sonogashira and Suzuki/Miyaura coupling reactions to synthesize <b>1</b> and <b>2</b> in high yields, respectively. Deprotection of <b>1</b> under acidic conditions provided the hydrazine hydrochloride salt <b>25</b>. The 17α-estradiol-tricarbonylrhenium(I) complex <b>4</b> was synthesized by labeling <b>25</b> with <i>fac</i>-[Re(OH<sub>2</sub>)<sub>3</sub>(CO)<sub>3</sub>]<sup>+</sup> 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.