Mass dose effects and in vivo affinity in brain PET receptor studies — a study of cerebral 5-HT4 receptor binding with [11C]SB207145

Attention to tracer dose principles is crucial in positron emission tomography (PET), and deviations can induce serious errors. In this study, we devise a method for determining receptor occupancy of the mass dose of the radioligand itself and the in vivo affinity. Methods: The approach was used for [11C]SB207145, a new PET radioligand for imaging the cerebral 5-HT4 receptors in humans. Test–retest PET studies with varying specific activities of [11C]SB207145 were conducted in seven healthy subjects, and the output parameter regional BPND was modeled. Individual occupancy plots were first computed to estimate the mass dose that saturates 50% of receptors (ID50), and subsequently, the maximal mass dose that can be injected (arbitrarily set at an occupancy <5%) was calculated. Scatchard plots were computed to estimate the in vivo KD. Results: Increasing the mass dose resulted in a decrease in BPND, whilst the relative cerebellar uptake was unchanged. The ID50 was 85.4±30.2 μg, and the upper mass dose limit was 4.5±1.6 μg, which does not require ultrahigh specific activity. The estimated in vivo KD was 2.8 nM (range 1.0–4.8), without any regional differences. Conclusion: The presented method for estimating the upper mass dose limit is suggested as part of validation of PET radioligands.