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Development of a non-radiometric method for measuring the arterial input function of a ¹¹C-labeled PET radiotracer.

ABSTRACT: Positron emission tomography (PET) uses radiotracers to quantify important biochemical parameters in human subjects. A radiotracer arterial input function (AIF) is often essential for converting brain PET data into robust output measures. For radiotracers labeled with carbon-11 (t_1/2 = 20.4 min), AIF is routinely determined with radio-HPLC of blood sampled frequently during the PET experiment. There has been no alternative to this logistically demanding method, neither for regular use nor validation. A ¹¹C-labeled tracer is always accompanied by a large excess of non-radioactive tracer known as carrier. In principle, AIF might be obtained by measuring the molar activity (A_m; ratio of radioactivity to total mass; Bq/mol) of a radiotracer dose and the time-course of carrier concentration in plasma after radiotracer injection. Here, we implement this principle in a new method for determining AIF, as shown by using [¹¹C]PBR28 as a representative tracer. The method uses liquid chromatography-tandem mass spectrometry for measuring radiotracer A_m and then the carrier in plasma sampled regularly over the course of a PET experiment. A_m and AIF were determined radiometrically for comparison. The new non-radiometric method is not constrained by the short half-life of carbon-11 and is an attractive alternative to conventional AIF measurement.

SUBMITTER: Shetty HU

PROVIDER: S-EPMC7562706 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:This was a first-in-human study of the PET radiotracer 11C-LSN3172176 for the muscarinic acetylcholine receptor subtype M1. The objectives of the study were to determine the appropriate kinetic model to quantify binding of the tracer to M1 receptors, and the reliability of the chosen quantification method. Methods: Six healthy subjects completed the test-retest protocol, and 5 healthy subjects completed the baseline-scopolamine blocking protocol. Multiple modeling methods were applied to calculate total distribution volume (V T) and nondisplaceable binding potential (BP ND) in various brain regions. The reference region was selected from the blocking study. The occupancy plot was applied to compute receptor occupancy by scopolamine and nondisplaceable distribution volume. Results: Tracer uptake was highest in the striatum, followed by neocortical regions and white matter, and lowest in the cerebellum. Regional time-activity curves were fitted well by all models. The 2-tissue-compartment (2TC) model fits were good, but the 2TC parameters often could not be reliably estimated. Because V T correlated well between the 2TC and 1-tissue-compartment (1TC) models after exclusion of unreliable estimates, the 1TC model was chosen as the most appropriate. The cerebellum showed the lowest V T, consistent with preclinical studies showing little to no specific binding in the region. Further, cerebellar V T did not change between baseline and blocking scans, indicating that the cerebellum is a suitable reference region. The simplified reference tissue model (SRTM) slightly underestimated 1TC BP ND, and the simplified reference tissue model 2 (SRTM2) improved BP ND estimation. An 80-min scan was sufficient to quantify V T and BP ND The test-retest study showed excellent absolute test-retest variability for 1TC V T (≤5%) and BP ND (≤10%). In the baseline and blocking studies, occupancy values were lower in the striatum than in nonstriatal regions, as may be attributed to differences in regional acetylcholine concentrations. Conclusion: The 1TC and SRTM2 models are appropriate for quantitative analysis of 11C-LSN3172176 imaging data. 11C-LSN3172176 displayed excellent test-retest reproducibility and is a highly promising ligand to quantify M1 receptors in the human brain.

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Development of a non-radiometric method for measuring the arterial input function of a 11C-labeled PET radiotracer.

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Development of a non-radiometric method for measuring the arterial input function of a ¹¹C-labeled PET radiotracer.