Quantification of the purinergic P2X₇ receptor with [¹¹C]SMW139 improves through correction for brain-penetrating...

Area of Science:

• Neuroscience
• Radiochemistry
• Pharmacology

Background:

• The P2X7 receptor (P2X7R) is a key target for assessing neuroinflammation.
• [11C]SMW139 is a radioligand used for in vivo imaging of P2X7R.
• Radiometabolites can affect the accuracy of in vivo quantification.

Purpose of the Study:

• To investigate the impact of radiolabeled metabolites on [11C]SMW139 quantification.
• To evaluate the accuracy of different compartment modeling approaches.
• To improve in vivo assessment of neuroinflammation using [11C]SMW139.

Main Methods:

• Ex vivo radioHPLC analysis of [11C]SMW139 parent and radiometabolite fractions in mouse and human plasma and brain.
• Positron Emission Tomography (PET) imaging in humans with arterial blood sampling.
• One- and two-tissue compartment (TCM) modeling with single and dual input functions to estimate the volume of distribution (VT).

Main Results:

• RadioHPLC revealed significant radiometabolite concentrations in plasma and brain homogenates.
• Dual input function modeling, accounting for brain-penetrant metabolites, yielded more precise estimates of [11C]SMW139 binding.
• Single input function modeling resulted in wide ranges and high coefficients of variation for VT estimates.

Conclusions:

• Compartment modeling incorporating brain-penetrant radiometabolites enhances the in vivo quantification of [11C]SMW139 binding to P2X7R.
• This improved quantification is crucial for accurate in vivo assessment of neuroinflammation.
• Dual input modeling offers a more reliable approach for P2X7R imaging studies.