Synthesis and lanthanum coordination of a BzMacropa analogue for convenient solid-phase peptide synthesis towards targeted alpha therapeutic discovery
Bibliographic record
Abstract
The alpha-emitting isotope actinium-225 is a promising radiometal for developing targeted alpha therapeutics (TAT) to treat malignant diseases. Actinium-225 has a half-life of 9.92 days and a decay chain emitting four alpha-particles. Alpha particle therapeutics are particularly attractive for their precise treatment while sparing surrounding tissue. Effective application of actinium-225 in radiopharmaceutical design requires a chelator that stably coordinates the metal and enables bioconjugation to targeting vectors. BzMacropa, a benzyl-fused diaza-18-crown-6 macrocyclic ligand, exhibits favorable binding properties but is incompatible with peptide-based radiopharmaceuticals synthesized using solid-phase peptide synthesis (SPPS) due to undesirable side reactions such as dimerization, offering limited conjugation flexibility. We report a synthetic route to a protected analogue of BzMacropa integrated with protected tert-butyl ester picolinic acid pendant arms with a free carboxylic acid handle enabling flexible conjugation strategies. The protected chelator was successfully synthesized at the multigram scale and was coupled to the C-X-C chemokine type 4 (CXCR4)-targeting peptide FC122 under SPPS conditions. The resulting conjugate was complexed with lanthanum (III), a non-radioactive surrogate for actinium-225. This work demonstrates a high-yielding, scalable synthesis and a modular platform for developing BzMacropa-peptide conjugates, providing an effective approach to the synthesis of next-generation peptide-based TAT 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 | 0.001 |
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".