High sensitivity laboratory based ¹⁴C analysis for drug discovery

An ultra-sensitive laser-based analytical technique, intracavity optogalvanic spectroscopy (ICOGS) providing extremely high sensitivity for detection of ¹⁴C-labeled carbon dioxide has been demonstrated. Obviating the need for scintillation counting and capable of replacing accelerator mass spectrometers (AMS), the technique can quantify zeptomoles of ¹⁴C in sub-micromole CO₂ samples. Based on the specificity of laser resonances, coupled with the sensitivity provided by standing waves in an optical cavity, and detection via impedance variations, limits of detection near 10^{-15 14}C/¹²C ratios have been obtained. With the use of a 15 Watt ¹⁴CO₂ laser, a linear calibration with samples from ≈10^-15 to ≈10^-11 in ¹⁴C/¹²C ratios was demonstrated. Calibrations become nonlinear over larger concentration ranges due to laser and ICOGS saturation effects and changes in equilibration time constants. Conditions, however, can be chosen to provide near linear response over different dynamic ranges. Drug discovery applications such as radiolabeling studies with extremely low specific activity, microdosing studies, and individualized sub therapeutic tests of drug metabolism typically involve samples having ¹⁴C/¹²C ratios in the approximate range of 1 to 100 × 10^-12. A laboratory instrument for that range will be small (table top), low maintenance and capable of being interfaced to GC or LC inputs.