Synthesis and preclinical characterization of 1-(6′-deoxy-6′-[ 18 F]fluoro-β- d -allofuranosyl)-2-nitroimidazole (β-6′-[ 18 F]FAZAL) as a positron emission tomography radiotracer to assess tumor hypoxia
“…(The bad leaving group nature of F – ions hinders base‐promoted transformation of fluorohydrins to epoxides.) Wanek and co‐workers used the same reagent combination for the ring opening of sugar‐derived epoxide 97 but under reflux conditions in toluene (Scheme ) …”
Section: Fluoride Ring Opening Of Oxiranesmentioning
The current minireview highlights the most relevant methodologies for the creation of fluorinated scaffolds accessed through transformations of three‐membered heterocycles (oxiranes and aziridines) involving their opening with various nucleophilic fluorinating agents reported over recent years. The purpose of the review is also to provide an overview of the ring‐opening synthetic practices with fluoride towards different functionalized, fluorine‐containing scaffolds with the focus on regioselectivity/regiocontrol and enantioselectivity including symmetric or unsymmetric monoheterocycles, cycloalkane‐fused oxiranes and aziridines.
“…(The bad leaving group nature of F – ions hinders base‐promoted transformation of fluorohydrins to epoxides.) Wanek and co‐workers used the same reagent combination for the ring opening of sugar‐derived epoxide 97 but under reflux conditions in toluene (Scheme ) …”
Section: Fluoride Ring Opening Of Oxiranesmentioning
The current minireview highlights the most relevant methodologies for the creation of fluorinated scaffolds accessed through transformations of three‐membered heterocycles (oxiranes and aziridines) involving their opening with various nucleophilic fluorinating agents reported over recent years. The purpose of the review is also to provide an overview of the ring‐opening synthetic practices with fluoride towards different functionalized, fluorine‐containing scaffolds with the focus on regioselectivity/regiocontrol and enantioselectivity including symmetric or unsymmetric monoheterocycles, cycloalkane‐fused oxiranes and aziridines.
“…[ 18 F]FAZA has not been identified in detail, yet it is assumed to be via passive diffusion, as an alpha-configurated nucleoside derivative should not be transported actively. It has been conceptualized in the past [13,14,15,16] that uptake and retention of 2-nitroimidazole-sugars in hypoxic tumor tissue can be altered by permutation of both, sugar moiety and stereochemistry at the anomeric carbon atom (2-nitroimidazole linked)—with the rationale to take advantage of transport mechanisms involving nucleoside transporters. Involvement of nucleoside transporters in the tissue uptake-process of 2-nitroimidazole-sugars was only investigated recently with β -allofuranose as C 6 -sugar [15].…”
Section: Introductionmentioning
confidence: 99%
“…It has been conceptualized in the past [13,14,15,16] that uptake and retention of 2-nitroimidazole-sugars in hypoxic tumor tissue can be altered by permutation of both, sugar moiety and stereochemistry at the anomeric carbon atom (2-nitroimidazole linked)—with the rationale to take advantage of transport mechanisms involving nucleoside transporters. Involvement of nucleoside transporters in the tissue uptake-process of 2-nitroimidazole-sugars was only investigated recently with β -allofuranose as C 6 -sugar [15]. Transport of nucleosides and nucleoside analog drugs is mediated by two unrelated protein families in humans, the SLC28 family of concentrative nucleoside transporters (hCNTs) and the SLC29 family of equilibrative nucleoside transporters (hENTs) [17].…”
The benefits of PET imaging of tumor hypoxia in patient management has been demonstrated in many examples and with various tracers over the last years. Although, the optimal hypoxia imaging agent has yet to be found, 2-nitroimidazole (azomycin) sugar derivatives—mimicking nucleosides—have proven their potential with [18F]FAZA ([18F]fluoro-azomycin-α-arabinoside) as a prominent representative in clinical use. Still, for all of these tracers, cellular uptake by passive diffusion is postulated with the disadvantage of slow kinetics and low tumor-to-background ratios. We recently evaluated [18F]fluoro-azomycin-β-deoxyriboside (β-[18F]FAZDR), with a structure more similar to nucleosides than [18F]FAZA and possible interaction with nucleoside transporters. For a deeper insight, we comparatively studied the interaction of FAZA, β-FAZA, α-FAZDR and β-FAZDR with nucleoside transporters (SLC29A1/2 and SLC28A1/2/3) in vitro, showing variable interactions of the compounds. The highest interactions being for β-FAZDR (IC50 124 ± 33 µM for SLC28A3), but also for FAZA with the non-nucleosidic α-configuration, the interactions were remarkable (290 ± 44 µM {SLC28A1}; 640 ± 10 µM {SLC28A2}). An improved synthesis was developed for β-FAZA. For a PET study in tumor-bearing mice, α-[18F]FAZDR was synthesized (radiochemical yield: 15.9 ± 9.0% (n = 3), max. 10.3 GBq, molar activity > 50 GBq/µmol) and compared to β-[18F]FAZDR and [18F]FMISO, the hypoxia imaging gold standard. We observed highest tumor-to-muscle ratios (TMR) for β-[18F]FAZDR already at 1 h p.i. (2.52 ± 0.94, n = 4) in comparison to [18F]FMISO (1.37 ± 0.11, n = 5) and α-[18F]FAZDR (1.93 ± 0.39, n = 4), with possible mediation by the involvement of nucleoside transporters. After 3 h p.i., TMR were not significantly different for all 3 tracers (2.5–3.0). Highest clearance from tumor tissue was observed for β-[18F]FAZDR (56.6 ± 6.8%, 2 h p.i.), followed by α-[18F]FAZDR (34.2 ± 7.5%) and [18F]FMISO (11.8 ± 6.5%). In conclusion, both isomers of [18F]FAZDR showed their potential as PET hypoxia tracers. Differences in uptake behavior may be attributed to a potential variable involvement of transport mechanisms.
“…Recently, we synthesized 2-nitroimadazole precursors derived from α - and β -2-deoxy-D-ribose and α - and β -D-allofuranose. The β -anomers were radiolabeled and deprotected to give tracers 7 [16] and 8 [17] so far and evaluated for imaging tumor hypoxia.Fig. 1Known 2-nitroimidazole-based [ 18 F]fluoro tracers
…”
Abstract2-Deoxy-D-ribose was converted to α/β-mixtures of methyl 3-O-acetyl- and methyl 3-O-benzoyl-2-deoxy-5-(p-toluenesulfonyl)-D-ribofuranosides. These were reacted with boron trichloride to generate ribofuranosyl chlorides, which afforded precursors for tracers to image tumor hypoxia on substitution with salts of 2-nitroimidazole. The anomeric ratio of the nucleosides was delicately influenced by the reaction conditions.Graphical abstract
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