MSACL 2025 Abstract

Synthesis of Labeled Antiepileptic Drugs to Be Used as Reference Standards for LC-MS/MS Based Therapeutic Drug Monitoring (TDM)

Lars Kattner, Erik Rauch, Patrick Mäder
Endotherm Life Science Molecules, Saarbruecken, Germany

Lars Kattner, PhD (Presenter) Endotherm GmbH

Presenter Bio: Lars Kattner founded Endotherm GmbH in 1999. He received his Ph.D. degree in Chemistry in 1991 from the Freie Universität Berlin (Germany) working with Prof. J. Mulzer on the development of novel stereoselective synthetic methods and their application to the synthesis of various natural products.

During a subsequent postdoctoral study with Dr. M.R. Uskokovic at the Medicinal Chemistry Department of Hoffmann-La Roche (Nutley, USA), he developed a new versatile methodology for the synthesis of vitamin D metabolites and steroids.

Afterwards, he joined the group of Prof. R.W. Hartmann at the Department of Pharmaceutical Chemistry of the Saarland University (Germany), where he has been involved in the development of new enzyme inhibitors to be used as potential drugs against hormone-mediated prostate cancer.

Relevant Financial Disclosures (within past 24 months, reported on Jun 30, 2025) No relevant financial relationship(s) to disclose. Conflict mitigation NOT REQUIRED.

INTRODUCTION:
Therapeutic drug monitoring (TDM), or measuring patient blood drug levels, is particularly important for correct dosing and avoidance of overdoses of therapeutics with undesirable side effect profiles, as it is true for antiepileptic drugs. For effective use of methods in practice, LC-MS/MS has been established as a gold standard in diagnostic routine. Reliable results are best achieved by the inclusion of stable isotope-labelled standards.

METHODS:
The synthesis of most antiepileptic drugs is well documented in the literature. However, for TDM, accordingly labelled molecules, in turn labelled multifold by deuterium or, favorably, by 13C are needed. Labelling can be achieved either by careful selection of commercially available labelled starting material, by using isotopically labelled alkylation reagents or by appropriate H/D-exchange reactions.

RESULTS:
Efficient syntheses of 11 examples of isotopically labelled antiepileptic drugs in a chemical purity of >95%, and >98% isotopic enrichment are described. Appropriate labelling is achieved either by using labelled starting material, labelled reducing agents (LiAlD4), labelled alkylation agents (D3CCI) or catalytic H/D-exchange reactions.

CONCLUSION:
Isotopically labeled drugs can by synthesized in high purity and >98% isotopic enrichment by application of established synthesis procedures found in the literature for the synthesis of the corresponding non-labelled drugs, in combination with an appropriate choice of commercially available labelled starting material, substrates, reagents, or catalytic H/D-exchange reactions.