Synthesis, in vitro and in vivo evaluation of 11C-O-methylated arylpiperazines as potential serotonin 1A (5-HT1A) receptor antagonist radiotracers
Bibliographic record
Abstract
Abstract Background Serotonin 1A (5-HT 1A ) receptors are implicated in the pathogenesis of several psychiatric and neurodegenerative disorders motivating the development of suitable radiotracers for in vivo positron emission tomography (PET) neuroimaging. The gold standard PET imaging agent for this target is [ carbonyl - 11 C]WAY-100635, labeled via a technically challenging multi-step reaction that has limited its widespread use. While several antagonist and agonist-based PET radiotracers for 5-HT 1A receptors have been developed, their clinical translation has been hindered by methodological challenges and/or and non-specific binding. As a result, there is continued interest in the development of new and more selective 5-HT 1A PET tracers having a relatively easier and reliable radiosynthesis process for routine production and with favorable metabolism to facilitate tracer-kinetic modeling. The purpose of the current study was to develop and characterize a radioligand with suitable characteristics for imaging 5-HT 1A receptors in the brain. The current study reports the in vitro characterization and radiosyntheses of three candidate 5-HT 1A receptor antagonists, DF-100 (1) , DF-300 (2) and DF-400 (3) , to explore their suitability as potential PET radiotracers. Results Syntheses of 1–3 and corresponding precursors for radiolabeling were achieved from isonicotinic, picolinic acid or picolino nitrile. In vitro binding studies demonstrated nanomolar affinity of the compounds for 5-HT 1A receptors. Binding of 1–3 for other biogenic amines, neurotransmitter receptors, and transporters was negligible with the exception of moderate affinities for α 1 -adrenergic receptors (4–6-fold less potent than that for 5-HT 1A receptor). Radioligands [ 11 C] 1 – 3 were efficiently prepared by 11 C- O -methylation of the corresponding phenolic precursor in non-decay corrected radiochemical yields of 7–11% with > 99% chemical and radiochemical purities. Dynamic PET studies in rats demonstrated negligible brain uptake of [ 11 C] 1 and [ 11 C] 2 . In contrast, significant brain uptake of [ 11 C] 3 was observed with an early peak SUV of 4–5. However, [ 11 C] 3 displayed significant off-target binding attributed to α 1 -adrenergic receptors based on regional distribution (thalamus>hippocampus) and blocking studies. Conclusion Despite efficient radiolabeling, results from PET imaging experiments limit the application of [ 11 C] 3 for in vivo quantification of 5-HT 1A receptors. Nevertheless, derivatives of compound 3 may provide a scaffold for alternative PET radiotracers with improved selectivity for 5-HT 1A receptors or α 1 -adrenergic receptors.
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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 | 0.000 | 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 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".