Preparation and preliminary bioevaluation of a ^99mTc(CO)₃‐glucose derivative prepared by a click chemistry route

Abstract

Development of a 99mTc-labelled glucose derivative as a single-photon emission computed tomography analogue to [ 18 F]-2-fluoro-2-deoxy-D-glucose (FDG) is considered of great interest. Herein, we present the synthesis and preliminary bioevaluation of a 99m Tc(CO) 3 -glucose derivative. Derivatization of glucose at C2 was achieved using the so-called 'click chemistry', forming a histidine-like, 1,4-disubstituted triazole adequate as donor atom system for Tc(I)-tricarbonyl complexes. Synthesis of the intermediate azide derivative was achieved by conventional organic chemistry. Because of the efficiency and selectivity of this cycloaddition, labelling was performed in 'one pot', adding the tricarbonyl precursor fac-[ 99m Tc(CO) 3 (H 2 O) 3 ] + to the same vial where the click reaction has taken place without any further purification. A single product with radiochemical purity higher than 90% was obtained. It was stable for at least 4 h in reaction milieu and exhibited high hidrophilicity (log P of À1.2) and low binding to plasma proteins (5 AE 1%). Biodistribution in C57BL/6 mice bearing induced Lewis murine lung carcinoma is characterized by low blood and liver uptake and rapid urinary excretion. 99m Tc complex showed moderate tumour uptake but significant retention until 2 h post-injection. Soft tissue clearance was fast leading to significantly higher uptake in tumour in comparison to muscle (p = 0.05) at all time points. Overall, biodistribution of our compound was very similar to that of [ 18 F]-FDG. However, tumour uptake was significantly higher for [ 18 F]-FDG, probably because of high hidrophilicity of our derivative that may hinder cell penetration. Similarity to biodistribution of FDG is a promising outcome, and modifications of the chelator and linker might improve biological results.

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

“…Proposed structure of 99m Tc‐L is depicted in Figure 2. According to the literature and our previous experience, reaction of the functionalized azide and the biologically active alkyne results in the formation of a 1,4‐disubstituted 1,2,3‐triazole–containing tridentate ligand system. Coordination occurs through the NNO donor‐atom set to provide a stable and neutral complex.…”

“…The reaction is highly efficient, occurs in aqueous medium, and is enantiomerically selective, thus minimizing cross reactions and making purification of products straightforward. This strategy has been previously applied by our group for the derivatization of different types of biomolecules with excellent results …”

Optimized syntheses of Fmoc azido amino acids for the preparation of azidopeptides

“…It is well known that the direct azidation of bromo compounds in DMF (CAS 68‐12‐2) is unfeasible because of the high basicity of NaN 3 . Therefore, for the introduction of N 3 moiety under mild conditions, we decided to apply trimethylsilyl azide (CAS 4648‐54‐8) in hexamethylphosphoramide (CAS 680‐31‐9) or DMF . However, we surprisingly only isolated from the reaction mixture starting compound 6 instead of 7 .…”

Click Chemistry and Radiochemistry: The First 10 Years

“…96–100 Fernandez et al, for example, developed a 99m Tc-labeled glucose derivative as an imaging probe for glucose metabolism. 97 Similarly, Struthers et al developed an elegant one-pot “click-to-chelate” synthesis of a 99m Tc-labeled thymidine analogue as a SPECT surrogate for the clinically successful proliferation marker 18 F–FLT. 98 Taken together, this work clearly demonstrates that 99m Tc-labeled tracers created using the “click-to-chelate” methodology demonstrate in vivo behavior that is comparable, and in some cases superior, to the current “gold standard” chelators for [ 99m Tc-(CO) 3 ] + : Nτ -derivatized histidine and Nα -acetylated histidine.…”