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.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.002 |
| 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 teacher head, 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".