Flexible Custom Synthesis for Stable Isotopic Labeling
Whether you require an internal standard for quantitative analysis in a clinical study, need to determine metabolic routes and rates, or require an assay substrate molecule that releases a labeled product distinct from the endogenous product molecules present in a cell or tissue sample, we can create a flexible custom synthesis that meets your stable isotopic labeling needs.
What is Isotopic Labeling?
Isotopic labeling is the process by which typically heavier chemical isotopes, those atoms with higher neutron counts, are incorporated into chemicals or potential future drugs, to generate an isotopically labeled version of the parent molecule. This new chemical entity is generally considered to be chemically identical to the parent molecule, but will feature a higher molecular weight, which allows it to be used as an analytical reference gold standard.
How Do We Prepare Isotopically Labeled Molecules?
Typically, we look to exploit the existing synthetic methodologies for efficiency, replacing key commercial building blocks with a suitable number of their isotopically labeled equivalents to achieve isotopic clarity in downstream analysis. Where this is not possible, our team will look to more bespoke synthetic solutions to achieve the desired labeling strategy.
Isotopic Labeling Service: Atomic Exchange of H, C, N, and O
Our team of experts readily advise and offer strategic solutions that account for likely sites of metabolism, minimizing the risk of subsequent loss of labeling within putative metabolites. You can expect expert design and execution of multi-step synthesis that meets the need of your program. On-site equipment at our state-of-the-art facilities ensures you receive rapid results.
We don’t require specific stable isotopes with the site of labeling identified. However, if you have these inputs, our isotopic labeling team can provide a quote for the custom synthesis of your compound, including any of the required reagents and the expected delivery timelines.
If you do not currently have a stable isotope standards plan, provide us with your current unlabeled target of interest and we will recommend a cost-effective stable isotope solution. If you require a specific region of the molecule to be labeled, just let us know. We’ll be happy to discuss your viable isotopic labeling options.
Isotopic Labeling Data Packages
You will need a GLP certificate of analysis (COA) to take the stable isotope-labeled compound through a clinical study as an internal reference standard. Charles River’s custom synthesis of stable isotope-labeled materials can be provided with a comprehensive data package that includes supporting analytical data to meet GLP standards and facilitate regulatory submission as required.
Additionally, all isotopic labeling materials are provided with a COA specifying:
- UPLC-MS purity
- 1H-NMR (13C, 19F, 15N, and 31P-NMR as required)
- A measure of isotopic enrichment ascertained by Q-TOF LC-MS
We can also write a final synthesis report for your stable isotope-labeled standard. We will be happy to produce your report in the agreed format, along with the COA upon request.
As our client, you retain exclusive rights to all the isotopic labeling data generated from your project. Extensive confidentiality practice and quality assurance (QA) processes protect your investment and ensure your data is secure.
Have a question for our chemists?
Accumulated Drug Discovery Knowledge
As programs progress, the synthetic chemistry team can access the resources from Charles River’s extensive portfolio, tapping into the knowledge of our organization's structural biology, in vitro biology, DMPK, in vivo pharmacology, pharmaceutics and formulation, and safety assessment teams to further support your project.
Frequently Asked Questions (FAQs) About Isotopic Labeling Services
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Do I need to provide synthetic routes to the unlabeled material?
Having the original synthesis of the unlabeled target can reduce timelines, but it is not essential. Our senior scientists are accustomed to meeting client objectives with innovative solutions.
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Can proton-deuterium exchange reduce isotopic enrichment leading to downstream trouble in LCMS/MS quantification studies?
We have extensive experience using deuterated standards as part of regulated studies. However, for some applications and compounds, deuterium might not be the right option for your stable isotope standard. In this case, we can advise on alternative labeling solutions such as C-13, N-15, and O-18.
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How many deuteriums do I need in my stable isotope-labeled standard?
The absolute number of stable isotopes required to be added to achieve isotopic clarity for quantitative analysis depends upon numerous factors, including the molecular weight of the target and the mass resolving power of the mass spectrometer being used for analysis. With typical lead or candidate drugs, it would usually be necessary to add ≥ 3 Daltons to ensure resolution from the parent ions. If you are unsure of your requirements, our isotopic standard labeling experts can recommend what you need.
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How much material do I need to order for isotopic labeling?
Having a single batch of a stable label standard from method identification to clinical study is optimal for quality and reporting. If you are unsure how much material you might need, consult with our team to help determine compound quantity.
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What are the typical levels of isotopic enrichment achieved with custom synthesized stable isotope-labeled targets?
Our synthetic chemists can utilize several options to achieve isotopic labeling, from targeted synthesis using stable isotope pool reagents to bespoke deuterium exchange. The exact synthetic solutions proposed will depend upon the chemical matter. Typically, our stable isotopic standards are provided at > 98% isotopic enrichment and come with a certificate of analysis (COA).