The H<sub>2</sub>S<i><sub>x</sub></i>macropa Series: Increasing the Chemical Softness of H<sub>2</sub>macropa with Sulfur Atoms to Chelate Radiometals [<sup>213</sup>Bi]Bi<sup>3+</sup> and [<sup>203</sup>Pb]Pb<sup>2+</sup> for Radiopharmaceutical Applications
Bibliographic record
Abstract
The effects of replacing nitrogen with sulfur atoms in the 18-membered macrocycle of the H 2 macropa chelator on the binding affinity and stability of “intermediate” (radio)metal [ 203 Pb]Pb 2+ and [ 213 Bi]Bi 3+ complexes are investigated. The 1,4,10,13-tetraoxo-7,16-diazacyclooctadecane backbone was replaced with derivatives containing sulfur in the 1,4- or the 1,4,10,13-positions to yield the novel chelators H 2 S 2 macropa (N 4 O 4 S 2 ) and H 2 S 4 macropa (N 4 O 2 S 4 ), respectively. Trends on the nat/203 Pb- and nat/213 Bi-complex stability constants, coordination chemistry, radiolabeling, and kinetic inertness were assessed via potentiometric titrations, UV–vis spectroscopy, NMR spectroscopy, X-ray crystallography and density functional theory (DFT) calculations. 1 H– 207 Pb NMR spectroscopy confirmed the involvement of backbone S and/or O donors in the metal coordination sphere. Overall, the trend demonstrated that increasing the softness of the donor atoms within the ligand backbone decreased the thermodynamic stability and kinetic inertness of both the Pb 2+ and Bi 3+ complexes. Conversely, DFT calculations with mock compounds dimethyl ether (DME) and dimethyl sulfide (DMS) demonstrated enhanced affinity of the S atom to both Pb 2+ and Bi 3+ with DMS compared to DME evinced by large Δ G ° values for both Pb 2+ and Bi 3+ complexes. The decreased stability of Pb/Bi–S x macropa ( x = 0, 2, 4) upon increased sulfur atom incorporation may be a result of the increased steric strain within the macrocyclic backbone upon sulfur atom introduction. Nonetheless, [ 203 Pb]Pb 2+ and [ 213 Bi]Bi 3+ labeling (pH = 7, 30 min reaction time; 10 –4 –10 –8 M chelator) resulted in both S 2 macropa 2– and macropa 2– attaining similarly high radiolabeling efficiency. Meanwhile, S 4 macropa 2– only possessed the ability to complex [ 213 Bi]Bi 3+ . Both [ 203 Pb][Pb(macropa)] and [ 203 Pb][Pb(S 2 macropa)] remained greater than 97% intact when challenged against human serum over 72 h. The results of this study reveal the effects of incorporating sulfur donor atoms into macrocyclic chelators for [ 203 Pb]Pb 2+ and [ 213 Bi]Bi 3+ radiopharmaceuticals.
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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".