Psychopharmacology (2004) 174:260–265 DOI 10.1007/s00213-003-1754-x ORIGINAL INVESTIGATION Katalin Marthi · Steen Jakobsen · Dirk Bender · Søren B. Hansen · Stefan Bo Smith · Flemming Hermansen · Raben Rosenberg · Donald F. Smith [N-methyl- 11 C]Mirtazapine for positron emission tomography neuroimaging of antidepressant actions in humans Received: 12 August 2003 / Accepted: 1 December 2003 / Published online: 15 January 2004  Springer-Verlag 2004 Abstract 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 a 2 -adreno- ceptors in selected regions of the living human brain. Objective: To determine the regional central biodistribu- tion and pharmacokinetics of [N-methyl- 11 C]mirtazapine in humans. Methods: Five healthy volunteers received an intravenous injection of [N-methyl- 11 C]mirtazapine for evaluating its metabolism, biodistribution and pharmaco- kinetics. Results: [N-methyl- 11 C]Mirtazapine entered the brain readily, with initial clearance from blood to tissue (K 1 ) ranging from 0.31 ml/ml/min in amygdala to 0.54 ml/ml/min in thalamus. The rate of metabolism of [N-methyl- 11 C]mirtazapine in the bloodstream was rela- tively slow, with 20–40% of [ 11 C]-derived radioactivity still present as parent compound at 60 min post-injection. The clearance of [N-methyl- 11 C]mirtazapine from the tissue compartment (k 2 ’) 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- 11 C]mirtazapine was markedly greater in hip- pocampus and amygdala (11.3–12.0) than in cerebellum (6.7), with intermediate levels in the thalamus (9.4). Conclusions: [N-methyl- 11 C]Mirtazapine has suitable properties for PET neuroimaging. We envision [N-meth- yl- 11 C]mirtazapine as a molecular probe for PET imaging of antidepressant actions at sites such as a 2 -adrenoceptors in the living human brain. Keywords Mirtazapine · PET neuroimaging · Antidepressant drug · NaSSA · Radioligand metabolism · Biodistribution · Pharmacokinetics · Human brain Introduction Mirtazapine is an effective antidepressant drug classified as a noradrenergic and specific serotonergic antidepressant (NaSSA) (Pinder 1997; Kent 2000; Olver et al. 2001; Blier 2003). Unlike most antidepressants, mirtazapine fails to inhibit monoamine reuptake (Nickolson et al. 1982; de Boer et al. 1988; Anttila and Leinonen 2001). Instead, antidepressant properties of mirtazapine are attributed primarily to inhibition of a 2 -adrenergic auto- and hetero- ceptors, which activates noradrenergic transmission and causes a concurrent secondary increase in serotonergic cell firing and serotonin release (de Boer 1996; Pinder 1997; Kent 2000). Our interest in studying central actions of antidepressant drugs by positron emission tomography (PET) induced us to radiolabel mirtazapine with C-11 (Marthi et al. 2002a and 2003). Previously, we noted in an animal model that [N-methyl- 11 C]mirtazapine has favor- able properties for PET neuroimaging (Marthi et al. 2002a). Moreover, we found that [N-methyl- 11 C]mirtaza- pine is as safe as most other PET radiopharmaceuticals for use in humans (Marthi et al. 2003). Now, we present our first PET findings on the pharmacokinetics and biodistri- bution of [N-methyl- 11 C]mirtazapine in the human brain. Materials and methods Subjects This study was approved by the Danish Medicines Agency, the ethics committee of Aarhus Municipality, and the Committee for K. Marthi · S. Jakobsen · D. Bender · S. B. Hansen · F. Hermansen PET Center, Aarhus University Hospital, Nørrebrogade 44, 8000 Aarhus C, Denmark S. B. Smith · R. Rosenberg · D. F. Smith ( ) ) Institute for Basic Research in Psychiatry, Department of Biological Psychiatry, Aarhus University Hospital, 8240 Risskov, Denmark e-mail: dsmith@inet.uni2.dk Tel.: +45-89493332 Fax: +45-89493020 K. Marthi Hungarian Academy of Sciences, Research Group of Technical Analytical Chemistry, Budapest University of Technology and Economics, Szt. GellØrt tØr 4, 1111 Budapest, Hungary