RATIONALE: Central norepinephrine transporter (NET) is one of the main targets of antidepressants. Although the measurement of NET occupancy has been attempted in humans, the outcomes have been inconclusive. OBJECTIVE: In this study, the occupancy of NET by different doses of an antidepressant, nortriptyline, was measured using positron emission tomography (PET) with (S,S)-[(18)F]FMeNER-D(2). MATERIALS AND METHODS: PET scans using (S,S)-[(18)F]FMeNER-D(2) were performed on six healthy men before and after oral administration of a single oral dose of nortriptyline (10-75 mg). After a bolus i.v. injection of (S,S)-[(18)F]FMeNER-D(2), dynamic scanning was performed for 0-90 min, followed by scanning for 120-180 min. The ratio of the thalamus-to-caudate areas under the curve (120-180 min) minus 1 was used as the binding potential (BP(ND)) for NET. NET occupancy was calculated as the percentage reduction of BP(ND). Venous blood samples were taken to measure the concentrations of nortriptyline just before injection of the tracer and at 180 min after the injection. RESULTS: Mean NET occupancies by nortriptyline were 16.4% at 10 mg, 33.2% at 25 mg, and 41.1% at 75 mg. The mean plasma concentration of nortriptyline was less than the lower limit of detection at 10 mg, 23.7 ng/mL at 25 mg, and 50.5 ng/mL at 75 mg. Estimated ED(50) 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 of 10-75 mg or plasma concentration was observed from 16% to 41%.
RATIONALE: Central norepinephrine transporter (NET) is one of the main targets of antidepressants. Although the measurement of NET occupancy has been attempted in humans, the outcomes have been inconclusive. OBJECTIVE: In this study, the occupancy of NET by different doses of an antidepressant, nortriptyline, was measured using positron emission tomography (PET) with (S,S)-[(18)F]FMeNER-D(2). MATERIALS AND METHODS: PET scans using (S,S)-[(18)F]FMeNER-D(2) were performed on six healthy men before and after oral administration of a single oral dose of nortriptyline (10-75 mg). After a bolus i.v. injection of (S,S)-[(18)F]FMeNER-D(2), dynamic scanning was performed for 0-90 min, followed by scanning for 120-180 min. The ratio of the thalamus-to-caudate areas under the curve (120-180 min) minus 1 was used as the binding potential (BP(ND)) for NET. NET occupancy was calculated as the percentage reduction of BP(ND). Venous blood samples were taken to measure the concentrations of nortriptyline just before injection of the tracer and at 180 min after the injection. RESULTS: Mean NET occupancies by nortriptyline were 16.4% at 10 mg, 33.2% at 25 mg, and 41.1% at 75 mg. The mean plasma concentration of nortriptyline was less than the lower limit of detection at 10 mg, 23.7 ng/mL at 25 mg, and 50.5 ng/mL at 75 mg. Estimated ED(50) 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 of 10-75 mg or plasma concentration was observed from 16% to 41%.
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