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
Jeffrey B. Arterburn
Cesear Corona
Kalla Venkateswara Rao
Kathryn E. Carlson
John A. Katzenellenbogen
10.1021/jo034780g.s001
https://acs.figshare.com/articles/journal_contribution/Synthesis_of_17-_-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/3700212
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.
2003-08-14 00:00:00
Re
hydrazine hydrochloride salt 25
derivative
breast
substrate
tert
synthesizing radiolabeled complexes
tumor
butyl hydrazodiformate
CO
estrogen
Tc
pyridine
receptor binding affinity