Mass dose effects and in vivo affinity in brain PET receptor studies--a study of cerebral 5-HT4 receptor binding with...

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.

The approach was used for [(11)C]SB207145, a new PET radioligand for imaging the cerebral 5-HT(4) receptors in humans. Test-retest PET studies with varying specific activities of [(11)C]SB207145 were conducted in seven healthy subjects, and the output parameter regional BP(ND) was modeled. Individual occupancy plots were first computed to estimate the mass dose that saturates 50% of receptors (ID(50)), 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 K(D).

Increasing the mass dose resulted in a decrease in BP(ND), whilst the relative cerebellar uptake was unchanged. The ID(50) 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 K(D) was 2.8 nM (range 1.0-4.8), without any regional differences.

The presented method for estimating the upper mass dose limit is suggested as part of validation of PET radioligands.