Norepinephrine transporter occupancy by antidepressant in human brain using positron emission tomography with (S,S)-[18F]FMeNER-D2
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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.
In this study, the occupancy of NET by different doses of an antidepressant, nortriptyline, was measured using positron emission tomography (PET) with (S,S)-[18F]FMeNER-D2.
Materials and methods
PET scans using (S,S)-[18F]FMeNER-D2 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)-[18F]FMeNER-D2, 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 (BPND) for NET. NET occupancy was calculated as the percentage reduction of BPND. Venous blood samples were taken to measure the concentrations of nortriptyline just before injection of the tracer and at 180 min after the injection.
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 ED50 was 76.8 mg of administration dose and 59.8 ng/mL of plasma concentration.
NET occupancy by nortriptyline corresponding to the administration dose of 10–75 mg or plasma concentration was observed from 16% to 41%.
KeywordsNorepinephrine transporter (S,S)-[18F]FMeNER-D2 Positron emission tomography Occupancy Nortriptyline
- Ichise M, Liow JS, Lu JQ, Takano A, Model K, Toyama H, Suhara T, Suzuki K, Innis RB, Carson RE (2003) Linearized reference tissue parametric imaging methods: application to [11C]DASB positron emission tomography studies of the serotonin transporter in human brain. J Cereb Blood Flow Metab 23:1096–1112CrossRefPubMedGoogle Scholar
- Innis RB, Cunningham VJ, Delforge J, Fujita M, Gjedde A, Gunn RN, Holden J, Houle S, Huang SC, Ichise M, Iida H, Ito H, Kimura Y, Koeppe RA, Knudsen GM, Knuuti J, Lammertsma AA, Laruelle M, Logan J, Maguire RP, Mintun MA, Morris ED, Parsey R, Price JC, Slifstein M, Sossi V, Suhara T, Votaw JR, Wong DF, Carson RE (2007) Consensus nomenclature for in vivo imaging of reversibly binding radioligands. J Cereb Blood Flow Metab 27:1533–1539CrossRefPubMedGoogle Scholar
- Kragh-Sorensen P, Hansen CE, Baastrup PC, Hvidberg EF (1976) Self-inhibiting action of nortriptylin's antidepressive effect at high plasma levels: a randomized double-blind study controlled by plasma concentrations in patients with endogenous depression. Psychopharmacologia 45:305–312CrossRefPubMedGoogle Scholar
- Logan J, Wang GJ, Telang F, Fowler JS, Alexoff D, Zabroski J, Jayne M, Hubbard B, King P, Carter P, Shea C, Xu Y, Muench L, Schlyer D, Learned-Coughlin S, Cosson V, Volkow ND, Ding YS (2007) Imaging the norepinephrine transporter in humans with (S, S)-[11C]O-methyl reboxetine and PET: problems and progress. Nucl Med Biol 34:667–679CrossRefPubMedGoogle Scholar
- Meyer JH, Wilson AA, Sagrati S, Hussey D, Carella A, Potter WZ, Ginovart N, Spencer EP, Cheok A, Houle S (2004) Serotonin transporter occupancy of five selective serotonin reuptake inhibitors at different doses: an [11C]DASB positron emission tomography study. Am J Psychiatry 161:826–835CrossRefPubMedGoogle Scholar
- Papakostas GI, Thase ME, Fava M, Nelson JC, Shelton RC (2007) Are antidepressant drugs that combine serotonergic and noradrenergic mechanisms of action more effective than the selective serotonin reuptake inhibitors in treating major depressive disorder? A meta-analysis of studies of newer agents. Biol Psychiatry 62:1217–1227CrossRefPubMedGoogle Scholar
- Sadock B, Sadock V (2007) Kaplan & Sadock's synopsis of psychiatry: behavioral sciences/clinical psychiatry. Lippincott Williams & Wilkins, PhiladelphiaGoogle Scholar
- Seneca N, Gulyas B, Varrone A, Schou M, Airaksinen A, Tauscher J, Vandenhende F, Kielbasa W, Farde L, Innis RB, Halldin C (2006) Atomoxetine occupies the norepinephrine transporter in a dose-dependent fashion: a PET study in nonhuman primate brain using (S, S)-[18F]FMeNER-D2. Psychopharmacology (Berl) 188:119–127CrossRefGoogle Scholar
- Takano A, Gulyas B, Varrone A, Karlsson P, Schou M, Airaksinen AJ, Vandenhende F, Tauscher J, Halldin C (2008a) Imaging the norepinephrine transporter with positron emission tomography: initial human studies with (S, S)-[18F]FMeNER-D2. Eur J Nucl Med Mol Imaging 35:153–157CrossRefPubMedGoogle Scholar