Abstract
BackgroundThe characterization of fast-decaying radiotracers that are labeled with carbon-11 (t1/2 = 20.38 min), including critical measurement of specific radioactivity (activity per mole at a specific time) before release for use in positron-emission tomography (PET), has relied heavily on chromatographic plus radiometric measurements, each of which may be vulnerable to significant errors. Thus, we aimed to develop a mass-specific detection method using sensitive liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) for identifying 11C-labeled tracers and for verifying their specific radioactivities.MethodsThe LC-MS/MS was tuned and set up with methods to generate and measure the product ions specific for carbon-11 species and M + 1 carrier (predominantly the carbon-13 isotopologue) in four 11C-labeled tracers. These radiotracers were synthesized and then analyzed before extensive carbon-11 decay. The peak areas of carbon-11 species and M + 1 carrier from the LC-MS/MS measurement and the calculated abundances of carbon-12 carrier and M + 1 radioactive species gave the mole fraction of carbon-11 species in each sample. This value upon multiplication with the theoretical specific radioactivity of carbon-11 gave the specific radioactivity of the radiotracer.ResultsLC-MS/MS of each 11C-labeled tracer generated the product ion peaks for carbon-11 species and M + 1 carrier at the expected LC retention time. The intensity of the radioactive peak diminished as time elapsed and was undetectable after six half-lives of carbon-11. Measurements of radiotracer-specific radioactivity determined solely by LC-MS/MS at timed intervals gave a half-life for carbon-11 (20.43 min) in excellent agreement with the value obtained radiometrically. Additionally, the LC-MS/MS measurement gave specific radioactivity values (83 to 505 GBq/μmol) in good agreement with those from conventional radiometric methods.Conclusions11C-Labeled tracers were characterized at a fundamental level involving isolation and mass detection of extremely low-abundance carbon-11 species along with the M + 1 carrier counterpart. This LC-MS/MS method for characterizing fast-decaying radiotracers is valuable in both the development and production of PET radiopharmaceuticals.
Highlights
The characterization of fast-decaying radiotracers that are labeled with carbon-11 (t1/2 = 20.38 min), including critical measurement of specific radioactivity before release for use in positron-emission tomography (PET), has relied heavily on chromatographic plus radiometric measurements, each of which may be vulnerable to significant errors
Method that we developed for identifying and measuring the specific radioactivity (SA) of 11C-labeled tracers, we report results on four radiotracers applied in human PET studies, namely [11C] PBR28, [11C]dLop, [11C]MePPEP, and [11C](R)-rolipram (Figure 1)
We illustrate the development of the procedure with the example of [11C]PBR28
Summary
The characterization of fast-decaying radiotracers that are labeled with carbon-11 (t1/2 = 20.38 min), including critical measurement of specific radioactivity (activity per mole at a specific time) before release for use in positron-emission tomography (PET), has relied heavily on chromatographic plus radiometric measurements, each of which may be vulnerable to significant errors. We aimed to develop a mass-specific detection method using sensitive liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) for identifying 11C-labeled tracers and for verifying their specific radioactivities. A suitable technique for this purpose must conclusively identify the radiotracer and provide specific radioactivity (SA), the ratio of the amount of radioactive compound (GBq) to the amount of compound (mol) in radioactive and non-radioactive forms (isotopologues) at a specific measurement time. An accurate determination of SA is critical in many applications especially where the radiotracer is intended to bind to low-density protein targets, such as neurotransmitter receptors, enzymes or transporters, or in specific cases where the radiotracer is pharmacologically very potent, such as some radiotracers for dopamine, nicotinic, or opiate receptors [6,7,8]
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