ORIGINAL INVESTIGATION Receptor occupancy of mirtazapine determined by PET in healthy volunteers Donald F. Smith & Bo S. Stork & Gregers Wegener & Steen Jakobsen & Dirk Bender & Hélène Audrain & Svend B. Jensen & Søren B. Hansen & Anders Rodell & Raben Rosenberg Received: 11 May 2007 / Accepted: 22 June 2007 / Published online: 25 July 2007 # Springer-Verlag 2007 Abstract Rationale Molecular tools are needed for assessing anti- depressant actions by positron emission tomography (PET) in the living human brain. Objectives This study determined whether [ 11 C]mirtazapine is an appropriate molecular tool for use with PET to estimate the magnitude of neuroreceptor occupancy produced by daily intake of mirtazapine. Methods This study used a randomised, double-blind, placebo-controlled, parallel-group, within-subject design. Eighteen healthy volunteers were PET-scanned twice with [ 11 C]mirtazapine; once under baseline condition and again after receiving either placebo or mirtazapine (7.5 or 15 mg) for 5 days. We determined kinetic parameters of [ 11 C] mirtazapine in brain regions by the simplified reference region method and used binding potential values to calculate receptor occupancy produced by mirtazapine. Results Serum concentrations of mirtazapine ranged from 33 to 56 nmol/l after five daily doses of 7.5 mg mirtazapine and were between 41 and 74 nmol/l after 15 mg mirtaza- pine. Placebo treatment failed to alter the binding potential of [ 11 C]mirtazapine from baseline values, whereas daily intake of mirtazapine markedly decreased the binding potential in cortex, amygdala and hippocampus. Receptor occupancy ranged from 74 to 96% in high-binding regions of the brain after five daily doses of 7.5 mg or 15 mg mirtazapine, whereas 17–48% occupancy occurred in low- binding regions. Conclusions [ 11 C]Mirtazapine together with PET can de- termine the degree of receptor occupancy produced by daily doses of mirtazapine in regions of the living human brain. Keywords Mirtazapine . Anti-depressant . PET . Binding potential . Receptor occupancy Introduction Mirtazapine is a multi-target, anti-depressant drug that enhances the neuronal release of monoamines without inhibiting monoamine uptake (de Boer 1996; de Boer et al. 1988; Kent 2003; Szegedi and Schwertfeger 2005). Our interest in studying central actions of anti-depressant drugs induced us previously to synthesise [ 11 C]mirtazapine and use it for positron emission tomography (PET). In several studies, we demonstrated that [ 11 C]mirtazapine has highly favourable properties for PET neuroimaging and that its binding reflects mainly alpha 2 -adrenoceptors implicated in mood disorders (Marthi et al., 2002b; Marthi et al. 2003; Marthi et al. 2004; Smith et al. 2006; Brunello et al. 2003). Currently, we view [ 11 C]mirtazapine as a potentially valuable molecular tool for assessing central anti-depressant actions by PET in humans. Mirtazapine therapy is often monitored by measuring the serum concentration of the drug, but some patients fail nonetheless to benefit from the treatment (Fava et al. 2001; Fava et al. 2006; Versiani et al. 2005; McGrath et al. 2006). We believe that therapeutic effects of mirtazapine may depend on drug actions in the brain that are not revealed by measuring only the concentration of the drug in the bloodstream. In particular, we assume that the receptor Psychopharmacology (2007) 195:131–138 DOI 10.1007/s00213-007-0877-x D. F. Smith (*) : B. S. Stork : G. Wegener : R. Rosenberg Center for Psychiatric Research, Psychiatric Hospital of Aarhus University, 8240 Risskov, Denmark e-mail: dfsmith@inet.uni2.dk S. Jakobsen : D. Bender : H. Audrain : S. B. Jensen : S. B. Hansen : A. Rodell PET Center, Aarhus University Hospital, 8000 Aarhus C, Denmark