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.
Arterburn
Jeffrey B
JB
Department of Chemistry and Biochemistry MSC 3C, New Mexico State University, P.O. Box 30001, Las Cruces, New Mexico 88003, USA. jarterbu@nmsu.edu
Corona
Cesear
C
Rao
Kalla Venkateswara
KV
Carlson
Kathryn E
KE
Katzenellenbogen
John A
JA
D000818:Animals; D001943:Breast Neoplasms / Q000000981:diagnostic imaging; D004958:Estradiol / Q000031:analogs & derivatives* / Q000138:chemical synthesis*; D005260:Female; D006801:Humans; D006834:Hydrazines / Q000138:chemical synthesis; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D007700:Kinetics; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D009942:Organometallic Compounds / Q000737:chemistry*; D011725:Pyridines / Q000138:chemical synthesis; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000138:chemical synthesis; D011960:Receptors, Estrogen / Q000187:drug effects / Q000378:metabolism; D012756:Sheep; D013667:Technetium / Q000737:chemistry; D014312:Trisaccharides / Q000138:chemical synthesis*; D014599:Uterus / Q000378:metabolism; D014867:Water
D006834:Hydrazines; D007202:Indicators and Reagents; D008024:Ligands; D009942:Organometallic Compounds; D011725:Pyridines; D019275:Radiopharmaceuticals; D011960:Receptors, Estrogen; D014312:Trisaccharides; C481825:beta-D-galactofuranosyl-(1-5)-beta-D-galactofuranosyl-(1-6)-D-galactofuranosy; C481824:beta-D-galactofuranosyl-(1-6)-beta-D-galactofuranosyl-(1-5)-D-galactofuranosy; C481925:fac-(Re(OH(2))(3)(CO)(3)); D014867:Water; D004958:Estradiol; D013667:Technetium