Analysis of labelled compounds by mass spectroscopy in the presence of heavy isotopes at natural abundance: the NAIC program

In support of the development of a new treatment for COPD, 2 C-14 labeled compounds were required for in vitro animal studies. The synthesis of nitrile [ C]-1 was completed in 3 steps from C-14 labeled 4-bromobenzonitrile in accord with the previously developed medicinal chemistry route. The second compound, 2, did not possess an arylnitrile as did 1, which made the synthetic design more complex. An advanced, unlabeled benzotriazole containing intermediate, 10, was synthesized in low yield over 3 steps and was subsequently reacted with K CN to give a mixture of diastereomers 12. Separation of the diastereomers followed by deprotection afforded [ C]-2 in a 13% radiochemical yield.

Section: Methodsmentioning

confidence: 99%

“…The specific activities of the products were determined by LC/MS using Isopat 2 to deconvolute the MS signals. 18,19 Liquid scintillation counting was performed with a Beckman LS 6500 scintillation counter. Preparative HPLC was conducted on a 19 × 250 mm Waters XBridge Prep C18 10 μ OBD using gradient elution unless otherwise specified.…”

Section: Generalmentioning

confidence: 99%

Synthesis of 2 C‐14 labeled cathepsin C inhibitors: The use of a cyanide to displace a Benzotriazole

Kingston

Bergare

Lönn

et al. 2017

“…Merck tritiated tracer, [ 3 H]compound A , and [1‐methyl, C 3 H 3 ]caffeine (ViTrax Co, Placentia CA, 19.8 Ci/mmol) were used as internal standards. Radiochemical purity (Agilent 1100 series HPLC, Agilent; Radiomatic 625TR, PerkinElmer), LC/MS‐derived specific activity (Agilent MSD) and radioactive solution count (TRI‐CARB 3100TR, PerkinElmer) for each were measured. Radio‐HPLC screening using six columns provided additional confidence that compound A 19 was radiochemically pure.…”

Section: Methodsmentioning

confidence: 99%

NMR‐based approach to the analysis of radiopharmaceuticals: radiochemical purity, specific activity, and radioactive concentration values by proton and tritium NMR spectroscopy

Schenk

Dormer

Hesk

et al. 2015

Compounds containing tritium are widely used across the drug discovery and development landscape. These materials are widely utilized because they can be efficiently synthesized and produced at high specific activity. Results from internally calibrated (3)H and (1)H nuclear magnetic resonance (NMR) spectroscopy suggests that at least in some cases, this calibrated approach could supplement or potentially replace radio-high-performance liquid chromatography for radiochemical purity, dilution and scintillation counting for the measurement of radioactivity per volume, and liquid chromatography/mass spectrometry analysis for the determination of specific activity. In summary, the NMR-derived values agreed with those from the standard approaches to within 1% to 9% for solution count and specific activity. Additionally, the NMR-derived values for radiochemical purity deviated by less than 5%. A benefit of this method is that these values may be calculated at the same time that (3)H NMR analysis provides the location and distribution of tritium atoms within the molecule. Presented and discussed here is the application of this method, advantages and disadvantages of the approach, and a rationale for utilizing internally calibrated (1)H and (3)H NMR spectroscopy for specific activity, radioactive concentration, and radiochemical purity whenever acquiring (3)H NMR for tritium location.

“…In case of two catalysts, each catalyst was added in 150 mol%. The level of deuterium incorporation was determined through mass spectrometric data analyzed via the NAIC software developed by Lockley et al …”

Section: Methodsmentioning

confidence: 99%

Alternative efficient tritium labeling of repaglinide

Vliegen

Haspeslagh

Verluyten

2012

There is a need for an efficient tritium labeling methodology for repaglinide to support numerous in vitro and in vivo studies. Numerous homogeneous and heterogeneous catalysts were screened for their capacity to tritiate repaglinide directly without the need to synthesize suitable precursors and to avoid multistep synthesis. In particular, boosting effects using a combination of homogeneous and heterogeneous catalysts were examined. Finally, a suitable method was selected for tritation and resulted in an efficient tritation of repaglinide via a heterogeneous catalyzed hydrogen-tritium exchange reaction with iridium black as the preferred catalyst.