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Area of Science:

• Neuroimaging
• Radiochemistry
• Pharmacokinetics

Background:

• Positron Emission Tomography (PET) imaging utilizes tracers like [18F]DPA-714 to investigate neuroinflammation.
• Inter-individual variability in tracer metabolism can affect the accuracy of PET scan interpretations.

Purpose of the Study:

• To evaluate how factors including concomitant medications, age, sex, body mass index (BMI), and 18-kDa translocator protein (TSPO) binding affinity influence [18F]DPA-714 metabolism and pharmacokinetics.
• To assess the impact of these factors on the plasma input function for PET imaging.

Main Methods:

• Quantified the non-metabolized fraction of [18F]DPA-714 in plasma from 201 subjects (patients and healthy controls) using solid-phase extraction.
• Correlated metabolic fractions and plasma concentrations with demographic, clinical, and genetic factors using multiple linear regression and non-parametric tests.
• Investigated the effect of co-medications on brain uptake and compared individual versus population-based input functions.

Main Results:

• Co-medications affecting CYP3A4 activity significantly altered [18F]DPA-714 metabolism (up to 88% variation).
• Metabolism decreased with age and BMI, and was faster in females than males; TSPO binding affinity did not affect metabolism.
• Whole-body PET showed high tracer uptake in TSPO-rich organs, with significantly lower uptake in low-affinity binders.

Conclusions:

• Concomitant medications (CYP3A4 inhibitors/inducers), TSPO genetic status, age, BMI, and sex are key contributors to inter-individual variability in [18F]DPA-714 metabolism and concentration.
• This variability can significantly impact the plasma input function and subsequent brain and peripheral uptake measurements in PET imaging.
• Accurate interpretation of [18F]DPA-714 PET scans requires consideration of these influencing factors.