Reference region modeling approaches for amphetamine challenge studies with [11C]FLB 457 and PET

Area of Science:

• Neuroscience
• Radiochemistry
• Psychiatry

Background:

• Positron emission tomography (PET) with [(11)C]FLB 457 is crucial for assessing extrastriatal dopamine D2/D3 receptor availability.
• Arterial input function (AIF) measurements are typically required for accurate PET modeling, posing a practical challenge.
• Reference region modeling offers a non-invasive alternative to AIF-based methods for quantifying radioligand binding.

Purpose of the Study:

• To evaluate the utility of simplified reference tissue models (SRTM and SRTM2) for estimating amphetamine-induced changes in [(11)C]FLB 457 binding in extrastriatal brain regions.
• To compare the performance of SRTM and SRTM2 against a two-tissue compartmental model (2TC) using the cerebellum as a reference region.

Main Methods:

• Six healthy tobacco smokers underwent [(11)C]FLB 457 PET scans at baseline and 3 hours post-amphetamine administration (0.4-0.5 mg/kg).
• Simplified reference tissue models (SRTM, SRTM2) and a 2-tissue compartmental model (2TC) were employed to analyze binding in extrastriatal regions of interest (ROIs).
• The cerebellum served as the reference region, with its distribution volume stability assessed between scan conditions.

Main Results:

• SRTM and SRTM2 showed consistent underestimation of binding compared to 2TC (26% and 9% respectively) in extrastriatal ROIs.
• Both SRTM and SRTM2 successfully detected significant decreases in [(11)C]FLB 457 binding post-amphetamine, reflecting dopamine release.
• The 2TC model did not detect significant changes in binding after amphetamine administration.

Conclusions:

• Simplified reference tissue models (SRTM and SRTM2) are sensitive to amphetamine-induced dopamine release in extrastriatal brain regions using [(11)C]FLB 457 PET.
• These models provide a viable, non-invasive approach for studying dopaminergic dysfunction in psychiatric disorders without requiring arterial input data.