Synthesis of 17-α-Substituted Estradiol-Pyridin-2-yl Hydrazine Conjugates as Effective Ligands for Labeling with Alberto's Complex fac-[Re(OH₂)₃(CO)₃]⁺ in Water

Abstract

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.

Detection of an estrogen derivative in two breast cancer cell lines using a single core multimodal probe for imaging (SCoMPI) imaged by a panel of luminescent and vibrational techniques

“…Conjugates involving metal-carbonyl complexes and estrogen derivatives are reported in the literature 45,46,60,[65][66][67] but, as far as we know, they were never used for infrared imaging. We previously showed that the rhenium tris-carbonyl moiety was reliable for sub-cellular IR-imaging 5,11 using the strong infrared absorptions of CO stretching (E and A 1 -bands in C 3v symmetry, respectively at 1915 cm À1 and 2025 cm À1 ).…”

Development and characterization of a 99mTc‐labeled Neuropeptide Y short analog with potential application in breast cancer imaging

“…One key advantage of technetium comes from its rich chemical behavior that can assume a large spectrum of structural arrangements, the most important being the [Tc(CO) 3 ] + (carbonyl), [TcN] 2+ (nitrido), and [ReTcO] 3+ (oxo) cores (Arterburn, Corona, Rao, Carlson, & Katzenellenbogen, ; Mull, Sattigeri, Rodriguez, & Katzenellenbogen, ; Neto et al, ; Takahashi et al, ; Wüst, Spies, & Johannsen, ; Xia et al, ). The selection of the adequate combination of metal core and chelator is essential to allow a fine‐tuning of the physicochemical and biological properties of the resulting radiopharmaceutical (Bandoli, Dolmella, Porchia, Refosco, & Tisato, ; Bolzati et al, ; Pasqualini & Duatti, ).…”

Improved Palladium‐Catalyzed Sonogashira Coupling Reactions of Aryl Chlorides

“…[3,4] Apart from material science, the construction of aryl alkynes plays an important role in the synthesis of complex molecules of pharmaceutical and agrochemical interest (e.g. 5, [5] 6, [6] 7 [7] ), even though the arylene-ethynylene structure itself does not often occur in natural products, which is in marked contrast to the corresponding vinylene-ethynylene motif. [8] However, the alkynylation of aromatic halides and subsequent cyclization is a widely used method for the synthesis of carbo- [9] and heterocycles [10] as well as intermediates of natural products.…”