[N-methyl-11C]Mirtazapine for positron emission tomography neuroimaging of antidepressant actions in humans

Rationale Many actions of antidepressant drugs cannot yet be studied using positron emission tomography (PET) neuroimaging due to lack of suitable radioligands. We believe that mirtazapine, radiolabeled with C-11, might be suitable for PET neuroimaging of ₂-adrenoceptors in selected regions of the living human brain.Objective To determine the regional central biodistribution and pharmacokinetics of [N-methyl-¹¹C]mirtazapine in humans.Methods Five healthy volunteers received an intravenous injection of [N-methyl-¹¹C]mirtazapine for evaluating its metabolism, biodistribution and pharmacokinetics.Results [N-methyl-¹¹C]Mirtazapine entered the brain readily, with initial clearance from blood to tissue (K₁) ranging from 0.31 ml/ml/min in amygdala to 0.54 ml/ml/min in thalamus. The rate of metabolism of [N-methyl-¹¹C]mirtazapine in the bloodstream was relatively slow, with 20–40% of [¹¹C]-derived radioactivity still present as parent compound at 60 min post-injection. The clearance of [N-methyl-¹¹C]mirtazapine from the tissue compartment (k₂) ranged from a low of 0.03 min^–1 in amygdala to a high of 0.06–0.07 min^–1 in thalamus and cerebellum. The volume of distribution (V_e) of [N-methyl-¹¹C]mirtazapine was markedly greater in hippocampus and amygdala (11.3–12.0) than in cerebellum (6.7), with intermediate levels in the thalamus (9.4).Conclusions [N-methyl-¹¹C]Mirtazapine has suitable properties for PET neuroimaging. We envision [N-methyl-¹¹C]mirtazapine as a molecular probe for PET imaging of antidepressant actions at sites such as ₂-adrenoceptors in the living human brain.