H<sub>2</sub><i>CHX</i>hox: Rigid Cyclohexane-Reinforced Nonmacrocyclic Chelating Ligand for [<sup>nat/67/68</sup>Ga]Ga<sup>3+</sup>
Bibliographic record
Abstract
A rigid chiral acyclic chelator H 2 CHX hox was synthesized and evaluated for Ga 3+ -based radiopharmaceutical applications; it was compared to the previously reported hexadentate H 2 hox to determine the effect of a backbone reinforced from adding a chiral 1S,2S-trans-cyclohexane on metal complex stability, kinetic inertness, and in vivo pharmacokinetics. NMR spectroscopy and theoretical calculation revealed that [Ga( CHX hox)] + showed a very similar coordination geometry to that of [Ga(hox)] +, and only one isomer in solution was observed by NMR spectroscopy. Solution studies showed that the modification results in a significant improvement in the exceptionally high thermodynamic stability of [Ga(hox)] + with a 1.56 log unit increase in stability constant (log K ML = 35.91(1)). More importantly, H 2 CHX hox showed very fast Ga 3+ complexation at physiological pH 7.4, and acid-assisted Ga 3+ complex dissociation kinetic studies (pH 1) in comparison with H 2 hox revealed a 50-fold increase of the dissociation half-life time from 73 min to 58 h. Fluorescence microscopy imaging study confirmed its cellular uptake and accumulation in endoplasmic reticulum and mitochondria. MTT studies indicated a quite low cytotoxicity of [Ga( CHX hox)] + over a large concentration range. Dynamic PET imaging studies showed no accumulation in muscle, lungs, bone, and brain, suggesting no release of free Ga 3+ ions. [ 68 Ga][Ga( CHX hox)] + is cleared from the mouse via hepatobiliary and renal pathways. Compared to [ 68 Ga][Ga(hox)] +, the increased lipophilicity of [ 68 Ga][Ga( CHX hox)] + enhanced heart and liver uptake and decreased kidney clearance. [ 67 Ga][Ga( CHX hox)] + SPECT/CT imaging and biodistribution study revealed good clearance from liver to gallbladder after 90 min and finally into feces after 5 h. No decomposition or transchelation was observed over the 5 h study. These results confirmed H 2 CHX hox to be an obvious improvement over H 2 hox and an excellent candidate in this new “ox” family for the development of radiopharmaceutical compounds.
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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 | 0.000 |
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".