NOREPINEPHRINE TRANSPORTER OCCUPANCY BY ANTIDEPRESSANT IN HUMAN BRAIN MEASURED USING POSITRON EMISSION TOMOGRAPHY WITH (S,S)-[18F]FMENER-D2

Objectives: Norepinephrine transporter (NET) is one of the main targets of antidepressants. Although serotonin transporter occupancy was reported to be over 80% at clinical doses of serotonin reuptake inhibitors (SSRIs) during the treatment of depression [1], NET occupancy by antidepressants in human brain has not been reported because of a lack of suitable radioligands for NET. (S,S)-[18F]FMeNER-D2 was recently developed as a radioligand for the measurement of NET binding with positron emission tomography (PET) [2,3]. In this study, we investigated the degree of NET occupancy by different doses of an antidepressant, nortriptyline, using PET and (S,S)-[18F]FMeNER-D2.Methods: Six healthy males (age 22 - 39 yrs; mean +- SD, 30.5 +- 6.3 yrs) participated in this study. PET scans with (S,S)-[18F]FMeNER-D2 were performed before and after oral administration of a single dose of nortriptyline on separate days. The nortriptyline doses were 10 mg, 25 mg, and 75 mg in two subjects each. After a bolus i.v. injection of 188.9 +- 4.2 MBq of (S,S)-[18F]FMeNER-D2, scanning was performed for 0 - 90 min (1 min*10, 2 min*15, 5 min*10), followed by scanning for 120 - 180 min (10 min*6). Regions of interests were drawn on the thalamus and caudate in each PET image. The thalamus was used as target region, and the caudate as reference region. Areas under the curve (AUCs) of radioactivity in the target and reference regions were calculated for 120 - 180 min. The ratio of the thalamus-to-caudate AUCs minus 1 was used as the binding potential (BPND) for NET. NET occupancy was defined as the percentage reduction of BPND. Venous blood samples were obtained to measure the concentrations of nortriptyline just before injection of the tracer and at 180 min after. This study was approved by the Ethics and Radiation Safety Committee of the National Institute of Radiological Sciences, Chiba, Japan. After complete description of this study, written informed consent was obtained from all subjects.Results: The mean NET occupancies by nortriptyline doses were 16.4 % at 10 mg, 33.2 % at 25 mg, and 41.1% at 75 mg, respectively. The mean plasma concentration of nortriptyline was 0 ng/ml at 10 mg, 23.7 ng/ml at 25 mg, and 50.5 ng/ml at 75 mg. Estimated ED50 (50% effective dose) was 76.8 mg of administration dose and 59.8 ng/ml of plasma concentration.Conclusions: NET occupancy by nortriptyline corresponding to the administration dose and plasma concentration was observed. To determine the optimal administration dose of nortriptyline for patients with depression, the relation between therapeutic effects and NET occupancy needs to be investigated in further studies.References: [1] Meyer JH et al. Am J Psychiatry 2004; 161: 826-35.[2] Takano A et al. Eur J Nucl Med Mol Imaging 2008; 35: 153-7. [3] Arakawa R et al. J Nucl Med 2008; 49: 1270-6.Brain \u2709 & Brain PET \u270