A radiolabeled agonist tracer, (11)C-CIMBI-5, was developed for PET imaging of the serotonin 2A (5-HT2A) receptor in the brain. In vitro assays showed CIMBI-5 is a high-affinity agonist at the 5-HT2A receptor. Ex vivo rat studies demonstrated a specific binding ratio of 0.77 ± 0.07 in the frontal cortex, which was reduced to cerebellar levels after ketanserin treatment, indicating selective binding. PET studies in pigs revealed a cortical binding potential of 0.46 ± 0.12 and a target-to-background ratio similar to the antagonist tracer (18)F-altanserin. Ketanserin treatment reduced cortical binding to cerebellar levels, confirming selective in vivo binding. (11)C-CIMBI-5 is a promising tool for investigating 5-HT2A agonist binding in the living human brain.
Microdosing uses very low, radionuclide-labeled drug doses for early human imaging or pharmacokinetic studies, requiring only a reduced preclinical toxicology package to lower cost and speed development. The approach limits exposure and risk by testing small populations for short periods. However, extrapolating results to therapeutic doses demands special attention to low-dose behavior, especially for small organic molecules versus protein therapeutics. The article reviews these aspects and discusses microdosing's role in drug development according to three pillars: tissue distribution and target access, target engagement, and induction of relevant tissue responses.
MDMA triggers neuronal activation in limbic projection areas involved in emotional processing, shown by localized increases in glucose metabolism measured with 18F-FDG fPET. Simultaneously, it causes global cerebral and extracerebral hemodynamic decreases detected by BOLD fMRI. The hemodynamic reductions strongly correlate with serotonin transporter occupancy and are of a nonneuronal, peripheral origin. Increased serotonin from SERT blockage leads to neurovascular uncoupling via direct vascular effects. These findings challenge interpretations of previous fMRI studies that suggested MDMA mainly inhibits brain activity, and recommend 18F-FDG fPET as a more robust measure for pharmacological research on psychedelics.