Synthesis and evaluation of HOPO-O8-Methyl-tetrazine as a bifunctional chelator for use in [89Zr]Zr4+, [161Tb]Tb3+ and [227Th]Th4+ radioimmunoconjugates
Bibliographic record
Abstract
The growing availability of new radiometals with favorable decay properties for cancer diagnosis and therapy highlights the need for chelators that can stably bind a variety of metal ions. 1-Hydroxy-2( 1 H)-pyridinones (1,2-HOPOs) are effective bidentate ligands with strong affinity for trivalent and tetravalent metals. In this study, we developed a bifunctional octadentate 1,2-HOPO chelator with a methyl tetrazine (Me-Tz) moiety, HOPO-O 8 -Me-Tz, and evaluated its coordination to [ 89 Zr]Zr 4+ , [ 161 Tb]Tb 3+ , and [ 227 Th]Th 4+ for theranostic applications. HOPO-O 8 -Me-Tz was conjugated to HER2/ neu targeting antibody Trastuzumab (Tmab), modified with transcyclooctene (TCO), using the inverse electron demand Diels-Alder (IEDDA) click reaction to yield HOPO-O 8 -Tmab. Radiolabeled conjugates were synthesized under mild conditions (30 min, ambient temperature) and evaluated in vitro and in vivo in SKOV-3 tumour-bearing nude mice. All radiometal complexes demonstrated high stability in serum over 7 days. In vivo , [ 89 Zr]Zr-, [ 161 Tb]Tb- and [ 227 Th]Th-HOPO-O 8 -Tmab showed high tumour uptake (9.87 ± 3.57, 11.29 ± 4.14 and 19.40 ± 5.40 %ID/g, respectively). Notably, [ 161 Tb]Tb- and [ 227 Th]Th-conjugates exhibited low bone uptake at 96 h post-injection, indicating excellent in vivo stability. The potential redistribution of the alpha-emitting daughter nuclide [ 223 Ra]Ra 2+ from [ 227 Th]Th-HOPO-O 8 -Tmab was assessed, revealing elevated 223 Ra in the bone and joint. These findings underscore the promise of HOPO-O 8 -Me-Tz as a versatile bifunctional chelator for next-generation theranostic radioimmunoconjugates, while also highlighting the importance of managing daughter radionuclide redistribution in alpha therapy.
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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) | 0.000 | 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".