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Tritium-Labeled Compounds in PET Tracer Discovery? A Case Study from Roche's Internal Monoacylglycerol Lipase
Martin R Edelmann1, Luca C Gobbi1, Svenja Schmalzbauer1
1Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., CH-4070 Basel, Switzerland.
ACS Chemical Neuroscience
|September 18, 2025
Summary
Tritium labeling offers a cost-effective early screening method for positron emission tomography (PET) tracer development, reducing reliance on specialized facilities. This approach accelerates the identification of promising PET tracer candidates for neurological targets like monoacylglycerol lipase (MAGL).
Area of Science:
- Radiochemistry and Nuclear Medicine
- Neuroscience and Pharmacology
- Preclinical Drug Development
Background:
- Positron Emission Tomography (PET) tracer development is resource-intensive, requiring specialized radiochemistry infrastructure and PET imaging facilities.
- Tritium (³H) labeling serves as a viable surrogate radioisotope for early-stage PET tracer candidate selection, offering advantages in handling and cost.
- Tritium's lower energy emissions simplify radiation safety protocols compared to short-lived PET nuclides like Carbon-11 (¹¹C) or Fluorine-18 (¹⁸F).
Purpose of the Study:
- To present a workflow for early-stage PET tracer development utilizing tritium labeling as a cost-effective alternative to full PET center infrastructure.
- To evaluate tritium-labeled monoacylglycerol lipase (MAGL) inhibitors for central nervous system (CNS) applications.
- To identify promising radioligand candidates for subsequent evaluation as PET imaging agents.
Main Methods:
- Synthesis and characterization of tritium-labeled MAGL inhibitors.
- Ex vivo evaluation of radioligand performance, including binding assays and autoradiography in rodent models.
- Comparison of newly synthesized ligands with literature-reported PET tracers for MAGL.
Main Results:
- Five in-house MAGL inhibitors were selected for tritium labeling from a pool of 617 compounds.
- Compound 9 exhibited a favorable pharmacological profile among the newly synthesized tritium-labeled ligands.
- Autoradiography revealed superior properties for a T-401 chemotype, indicating its potential as a PET tracer candidate.
Conclusions:
- Tritium labeling provides an efficient and accessible method for the initial screening and optimization of PET tracer candidates.
- This workflow effectively bridges preclinical research with clinical translation by identifying promising ligands for further PET center evaluation.
- The presented approach accelerates the discovery of novel PET tracers for targets such as MAGL in the CNS.
