Synthesis of Radiolabelled Compounds for Clinical Studies

Atzrodt, Jens; Derdau, Volker; Loewe, Claudia

doi:10.1007/978-3-319-68864-0_12

Cited by 4 publications

(4 citation statements)

References 62 publications

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“…Peptides can be labelled with radioactive 14 C to track the passage of the biomolecule through a biological system . The manufacture of these 14 C‐peptides is custom made to the clients' requirements, with regard to the position of the labelled amino acid.…”

Section: Discussionmentioning

confidence: 99%

Synthesis of carbon‐14–labelled peptides

Dell'Isola

Brown

Jones

et al. 2019

Labelled Comp Radiopharmac

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Carbon‐14 (14C)–labelled active pharmaceutical ingredients (APIs) and investigational medicinal products (IMPs) are required for phase 0/I to phase III mass balance and micro‐dosing clinical trials. In some cases, this may involve the synthesis of 14C‐labelled peptides, and the analysis can be performed by accelerated mass spectrometry (AMS). The 14C‐peptide is typically prepared by the solid‐phase peptide synthesis (SPPS) approach using custom‐made glassware for the key coupling steps. Further modification of the purified 14C‐peptide can then be performed.

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Section: Discussionmentioning

confidence: 99%

Synthesis of carbon‐14–labelled peptides

Dell'Isola

Brown

Jones

et al. 2019

Labelled Comp Radiopharmac

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“…These decomposition rates are influenced by storage temperatures, specific activity, and molecular structure. To mitigate inherent instability issues, radiolabeled compounds are generally stored at low temperatures (≤ −20 °C or ≤ −70 °C) or as a solution in a solvent such as ethanol (Atzrodt et al 2020). Nevertheless, re-purification may be inevitable in instances where there is longer duration between radiolabeled compound synthesis and clinical study dosing.…”

Section: Introductionmentioning

confidence: 99%

CMC development of [14C]-labeled sotorasib for the conduct of microtracer human ADME study

et al. 2023

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Human absorption, distribution, metabolism, and excretion (hADME) studies of new drugs are required for global regulatory filings. Recent advances in high sensitivity analytical technologies have enabled microtracer hADME studies wherein very low radioactive doses can be administered to healthy volunteers to study drug pharmacokinetic profile. Microtracer hADME studies are advantageous to accelerate study timelines during drug development. However, there are limited examples in peer-reviewed journals that highlight the key chemistry, manufacturing, and control (CMC) development challenges and requirements for enabling these clinical microtracer hADME studies. The current manuscript summarizes the CMC activities, risk assessment, and mitigation strategies that were put in place and executed to enable and accelerate the microtracer hADME study of [14C]-labeled sotorasib (AMG 510, compound 1). Sotorasib is a first in class KRASG12C inhibitor used to treat non-small cell lung cancer (NSCLC) in patients with a KRASG12Cmutation (Canon et al., Nature 575:217–223, 2019). The key CMC activities included the synthesis of low nanocurie [14C]-labeled AMG 510 drug substance, development of a drug-in-bottle (DIB) formulation, use of simulation software to predict absorption profiles, associated drug substance and drug product analytical control strategies development, and the utilization of accelerator mass spectrometry (AMS) as a CMC tool enabling low radioactive strength formulation analysis.

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“…This starting material is transformed into four major derivatives from which all 14 C building blocks derive, namely, 14 C-carbon dioxide ([ 14 C]CO 2 ), metal 14 C-cyanides ([ 14 C]MCN), 14 C-acetylene, and 14 C-cyanamide ([ 14 C]BaN-CN). 50 These primary building blocks are further converted into more complex secondary intermediates such as [ 14 C]CH 3 OH or H[ 14 C]COOK. Of course, even more sophisticated precursors can be prepared such as mono- or multilabeled aromatic rings ( Scheme 1 , top).…”

Section: Introductionmentioning

confidence: 99%

“…After treatment, this nuclear reaction leads to the isolation of barium carbonate Ba[ 14 C]CO 3 as the first carbon-14 building block in organic radiosynthesis. This starting material is transformed into four major derivatives from which all 14 C building blocks derive, namely, 14 C-carbon dioxide ([ 14 C]CO 2 ), metal 14 C-cyanides ([ 14 C]MCN), 14 C-acetylene, and 14 C-cyanamide ([ 14 C]BaN-CN) . These primary building blocks are further converted into more complex secondary intermediates such as [ 14 C]CH 3 OH or H[ 14 C]COOK.…”

Section: Introductionmentioning

confidence: 99%

Late-Stage Carbon-14 Labeling and Isotope Exchange: Emerging Opportunities and Future Challenges

Babin

Taran

2022

JACS Au

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Carbon-14 ( 14 C) is a gold standard technology routinely utilized in pharmaceutical and agrochemical industries for tracking synthetic organic molecules and providing their metabolic and safety profiles. While the state of the art has been dominated for decades by traditional multistep synthetic approaches, the recent emergence of late-stage carbon isotope labeling has provided new avenues to rapidly access carbon-14-labeled biologically relevant compounds. In particular, the development of carbon isotope exchange has represented a fundamental paradigm change, opening the way to unexplored synthetic transformations. In this Perspective, we discuss the recent developments in the field with a critical assessment of the literature. We subsequently discuss research directions and future challenges within this rapidly evolving field.

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Synthesis of Radiolabelled Compounds for Clinical Studies

Cited by 4 publications

References 62 publications

Synthesis of carbon‐14–labelled peptides

Synthesis of carbon‐14–labelled peptides

CMC development of [14C]-labeled sotorasib for the conduct of microtracer human ADME study

Late-Stage Carbon-14 Labeling and Isotope Exchange: Emerging Opportunities and Future Challenges

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