IC‐P‐051: Synthesis and Evaluation of Butyrylcholinesterase Ligands for Neuroimaging Alzheimer's Disease
Bibliographic record
Abstract
Butyrylcholinesterase (BuChE) is a serine hydrolase enzyme that, along with acetylcholinesterase (AChE), catalyzes the hydrolysis of acetylcholine. Increased levels of BuChE are observed in Alzheimer's disease brain especially in neuritic plaques and neurofibrillary tangles, characteristic of the disease. This makes BuChE a suitable target for disease-specific neuroimaging. Cholinesterase ligands currently being investigated for imaging have the radioisotope in that part of the molecule that is the initial leaving group in the enzyme catalyzed hydrolysis. This may be, in part, responsible for poorly defined images with these ligands. We propose that BuChE-specific radiopharmaceuticals, having the radioisotope in the part of the molecule that forms the ligand-enzyme intermediate, can be used in PET and SPECT imaging to detect this enzyme in vivo, and thus the neuritic plaques and neurofibrillary tangles associated with AD. Imaging the AD plaques and tangles may provide an early diagnosis as well as a method for treatment monitoring. Piperidinols and pyrrolidinols were reacted with various acid chlorides and isocyanates to produce corresponding esters and carbamates, respectively. These compounds were evaluated using enzyme kinetics for their affinity towards both BuChE and AChE. BuChE-specific ligands were then transformed into intermediates suitable for incorporation of a radiolabel, either I for SPECT or F for PET imaging. Carrier free radiolabeled ligands were then administered to experimental animals and the distribution of BuChE in vivo determined. Several piperidinols and pyrrolidinols proved to be specific ligands for BuChE. These ligands were successfully transformed into both tin and tosylate intermediates. I was successfully incorporated into these molecules. Preliminary animal imaging indicated regional distribution of ligands. BuChE has been previously demonstrated to be involved in the pathology of AD. We have synthesized several BuChE-specific ligands that have been successfully radiolabeled. Preliminary animal imaging with these ligands indicated that there is regional distribution in the body and that these ligands are taken up into the brain. Further refinement of imaging methodology is underway. The imaging of BuChE in vivo may facilitate early diagnosis and treatment monitoring of AD.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 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".