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  • Open access
  • 85 Reads
Sulfur [18F]fluoride Exchange Reaction Enables Rapid Access to 18F-Labeled PET Tracers

Efficient 18F-fluorination procedures for the production of radiopharmaceuticals are urgently needed to satisfy the increasing demand for clinical diagnostics using positron emission tomography (PET). However, the development of PET tracers is often a time-consuming and challenging process. This work examines the applicability of the recently described sulfur [18F]fluoride exchange ([18F]SuFEx) chemistry as a fast-screening approach towards a number of clinically-relevant PET tracer preparations.

The preparation of a number of 18F-labeled compounds commenced with [18F]fluoride loading onto a QMA-cartridge, which was eluted with a methanolic solution containing a base, followed by solvent removal under reduced pressure. Thereafter, the radiolabeling precursors in MeCN were added to the reaction vessels, and allowed to react via [18F]SuFEx at room temperature for 5 min. The radiofluorination reactions were quenched by water dilution followed by C18 cartridge purification. The 18F-labeled products were isolated by elution from the cartridge with EtOH and the identities of the products were confirmed by radio-UHPLC.

The optimized preparations of 18F-labeled PSMA inhibitor, PD-L1 ligand, COXIB, and FAPI were accessed with high non-decay corrected isolated activity yields (AY) of 33-57% (n = 12) and >95% radiochemical purity (RCP) in 25 min. The automated radiosynthesis procedures afforded the radiolabeled products in an unoptimized 8-15% AY (n = 5), with >95% RCP in 40 min.

The ultra-fast [18F]SuFEx reaction has permitted several structurally-diverse 18F-labeled compounds for potential imaging to be rapidly accessed in excellent isolated AYs and high RCP. Presently, optimization of the automated radiosynthesis and biological assessment of the 18F-labeled products is underway.

  • Open access
  • 21 Reads
Study of cytotoxicity of spiro-fused [3-azabicyclo[3.1.0]hexane]oxindoles against tumor cell lines

Oncological diseases are one of the most common public health problems and second leading cause of death after cardiovascular disease. Natural products or synthetic compounds inspired from natural products continue to be excellent sources for new drug candidates. Recent advances in synthesis of complex heterocyclic systems have led to significant increase in interest in development of efficient methods for synthesis of thereof as potential drugs or biological probes. Oxindole, azabicyclohexane and pyrrolizine units are known heterocyclic motifs that form core of a large family of alkaloid natural products with strong bioactivity profiles.

Series of heterocyclic compounds containing 3-spiro[3-azabicyclo[3.1.0]hexane]oxindole framework have been studied for their antiproliferative activity against K562, Jurkat, HeLa, CT26 cell lines. This spiro-fused adducts are readily available via one-pot three-component 1,3-dipolar cycloaddition reactions of cyclopropenes and azomethine ylides (generated in situ from amino acids and oxindoles). In agreement with DNA cytometry studies, the tested compounds have achieved significant cell-cycle perturbation with higher accumulation of cells in G0/G1 phase. Using confocal microscopy, we found that actin filaments disappeared and granular actin was distributed diffusely in the cytoplasm in up to 40% of treated cells. Also we discovered that number of cells with filopodium-like membrane protrusions was significantly reduced after treatment with some of tested compounds (from 92 % in control cells up to 36% after treatment). The obtained results support the antitumor effect of the studied compounds and encourage the extension of the study in order to improve the anticancer activity and reduce the toxicological risks of obtained compounds.

  • Open access
  • 21 Reads
Genetically encoded photosensibilizer targeted to methylated DNA

Genetically encoded photosensibilizers are widely used in fundamental research and translational medicine due to their ability to generate reactive oxygen species (ROS) after photosensitizing. Previously, it was shown in mice that red dimeric fluorescent protein KillerRed is a potential photosensitizer that can be used for photodynamic therapy of cancer (Shirmanova, 2018). Also, it was demonstrated that HeLa cells expressing KillerRed fuzed to histone H2B cease proliferation upon illumination (Serebrovskaya, 2011). DNA repair protein X-ray repair cross-complementing protein 1 (XRCC1) redistributed in the cell nuclei, indicating that the mechanism of phototoxic action of the construct involved DNA breaks generation.

Now we have constructed and tested a new genetically encoded photosensibilizer molecule which introduces DNA breaks and activates the repair system in cancer-derived and embryonic cell lines more efficiently than previously described. The molecule consists of two parts: a SuperNova2 (monomeric mutant of KillerRed with enhanced phototoxicity (Gorbachev, 2020)) and methyl-CpG binding protein MECP2. The complex activates XRCC1 redistribution after illumination with lower power compared to the previously used construct. We suppose it can be explained by the tighter contact between photosensibilizer and DNA. Also, we hypothesize that the system should be error-prone for the expressed genes as it is targeted to the DNA which is silenced by methylation.

Taking everything into consideration, the new genetically encoded construct has shown the improved ability to generate DNA breaks in the cancer cell lines.

Supported by the RSF 22-14-00141 grant.