Development and characterization of a ^99mTc‐tricarbonyl–labelled estradiol derivative obtained by “Click Chemistry” with potential application in estrogen receptors imaging

Abstract

Assessment of the presence of estrogen receptors in breast cancer is crucial for treatment planning. With the objective to develop a potential agent for estrogen receptors imaging, we present the development and characterization of a Tc-tricarbonyl-labelled estradiol derivative. Using ethinylestradiol as starting material, an estradiol derivative bearing a 1,4-disubstituted 1,2,3-triazole-containing tridentate ligand system was synthesized by "Click Chemistry" and fully characterized. Labelling with high yield and radiochemical purity was achieved through the formation of a Tc-tricarbonyl complex. The radiolabelled compound was stable, exhibited moderate binding to plasma protein (approximately 33%) and lipophilicity in the adequate range (logP 1.3 ± 0.1 at pH 7.4). Studies in MCF7 showed promising uptake values (approximately 2%). However, more than 50% of the activity is quickly released from the cell. Biodistribution experiments in normal rats confirmed the expected "in vivo" stability of the radiotracer but showed very high gastrointestinal and liver activity, which is inconvenient for in vivo applications. Taking into consideration the well-documented influence of the chelating system in the physicochemical and biological behaviour of technetium-labelled small biomolecules, research will be continued using the same pharmacophore but different complexation modalities of technetium.

Synthesis of a [18F]F Estradiol Derivative via Click Chemistry Using an Automated Synthesis Module: In Vitro Evaluation as Potential Radiopharmaceutical for Breast Cancer Imaging

“…This reaction occurred in an aqueous medium and was catalyzed by Cu(I). Cu (I) was generated in situ by the action of ascorbic acid in the presence of Cu(II) [ 7 , 13 , 14 ]. After 6 days of reaction, extractions with ethyl acetate were carried out, and C was obtained with a yield higher than 100% due to the presence of residual ethinylestradiol and salts in the crude reaction.…”

“…In fact, 1,4-functionalized 1,2,3-triazoles are potentially versatile ligands offering several donor sites for metal coordination and have been extensively applied to the preparation of potential 99m Tc radiopharmaceuticals [ 8 , 9 , 10 ]. Our group has utilized this method for the synthesis of glucose, nitroimidazole, flutamide, and estradiol derivatives for technetium labeling ( Figure 1 ) [ 11 , 12 , 13 , 14 , 15 , 16 ].…”

Click Chemistry and Radiochemistry: An Update

“…In this technique, a CuAAC ligation between azide- and alkyne-bearing substrates creates a bespoke chelator in which the 1,2,3-triazole participates in the coordination of the radiometal as a ligand with both σ-donor and π-acceptor character. This approachdubbed “Click-to-Chelate” when it was first reported in 2006has most famously been used to create tridentate chelators for radiolabeling with Tc­(I) cores like [ 99m Tc]­[Tc­(CO) 3 (H 2 O) 3 ] + but has been employed with Re­(I) synthons as well. − Recently, Mindt and co-workers used this approach to synthesize 99m Tc-labeled probes in which the radiometal is sequestered by a tripodal N 2 O-based architecture created via the reaction of N α -propargyl lysine with an azide-bearing vector (Figure A). , Others have taken a similar approach to creating probes in which 99m Tc­(I) is coordinated by N 2 O- and NSO-containing coordination structures, most notably a multimodal, PSMA-targeted theranostic designed to facilitate both SPECT imaging and photodynamic therapy. ,− In yet another example, Erfani et al created a 99m Tc-labeled agent for the visualization of 5HT 1A serotonin receptors in the brain by clicking together 2-ethynylpyridine and an azide derived from 1-(2-methoxyphenyl)­piperazine (Figure B). The 99m Tc-labeled probe displayed brain uptake of 1.4 ± 0.1 %ID/g 15 min post-administration with hotspots in the 5HT 1A -active hippocampus .…”

Development and Evaluation of 99mTc Tricarbonyl Complexes Derived from Flutamide with Affinity for Androgen Receptor

“…Our group has a wide experience in the designing of potential 99m Tc radiopharmaceuticals bearing the [Tc(CO) 3 ] + core for different oncological applications [ 17 , 18 , 19 , 20 ]. This core is a very convenient synthon for the labeling of small biomolecules due to its high stability, the diversity of potential donor groups (amines, thioethers, thiols, N-heterocycles, etc.…”