Synthesis, transportability and hypoxiaselective binding of 1-beta-D-(5-Deoxy-5-fluororibofuranosyl)-2-nitroimidazole (beta-5-FAZR), a configurational isomer of the clinical hypoxia marker, FAZA.
Bibliographic record
Abstract
PURPOSE: Cellular uptake of most azomycin-based radiosensitizers depends on perfusion and diffusion, rather than on active transport. In medical imaging using radioisotopically labeled azomycin nucleosides, image contrast depends on rapid diffusion from normoxic tissues and rapid renal clearance from the central compartment. [18F]FAZA [1-alpha-D-(5-deoxy-18F]fluoroarabinofuranosyl)-2-nitroimidazole], an azomycin nucleoside currently under clinical evaluation as a marker of tissue hypoxia in medical centers world wide, provides high contrast but its uptake is diffusion dependent and therefore low. 1-D-(5-Fluoro-5-deoxyribofuranosyl)-2-nitroimidazole 6 (beta-5-FAZR), a Beta-ribose analog of FAZA, has now been developed to exploit transport across cell membranes to improve absolute uptake in hypoxic regions and high contrast. METHODS: Beta-5-FAZR was synthesized by classical sugar base coupling followed by regioselective fluorination. In radiosensitization of hypoxic and normoxic to 60Co x-rays was determined relative to known radiosensitizers. The relative abilities of five human nucleoside transporters (hENT1/2, hCNT1/2/3 to bind the radiosensitizers were determined by quantifying their inhibition of uridine transport by recombinant transporters produced in yeast. RESULTS: Beta-5-FAZR was synthesized in 44 percent yield. Beta-5-FAZR had moderate radiosensitization effect on human HCT116/100 colorectal carcinoma (OER 1.8). Beta-5-FAZR was a weak inhibitor of uridine transport relative to nonfluorinated 1-beta-D-(ribofuranosyl)-2-nitroimidazole (beta-AZR). CONCLUSION: Facile synthesis of beta-5-FAZR was achieved and its activity as a radiosensitizer was confirmed. Substitution of C-5 hydroxyl by fluorine in the ribose moiety greatly reduced interaction with hENT1/2 and hCNT1/2 and moderately reduced interaction with hCNT3 relative to thymidine and beta-AZR.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".