Acute occupancy of brain serotonin transporter by sertraline as measured by [11C]DASB and positron emission tomography.
BACKGROUND
In vivo determination of serotonin transporter (5-HTT) occupancy by selective serotonin reuptake inhibitors (SSRI) using positron emission tomography (PET) can aid in determination of dosing. Previous studies used chronic SSRI administration that may down-regulate 5-HTT and used the cerebellum as reference region despite measurable 5-HTT. We examine the reference region and occupancy after acute sertraline dosing.


METHODS
We conducted autoradiography of human postmortem cerebellum to determine an optimal reference region. We quantified 5-HTT binding using [(11)C]DASB and arterial input functions in 17 healthy volunteers. Baseline PET scans were followed by a scan 4-6 days after 25 mg to 100mg of daily sertraline. Several modeling methods and outcome measures were assessed.


RESULTS
Cerebellar gray matter is the optimal reference region. Occupation of 5-HTT sites saturates at low plasma sertraline levels (K(D) = 1.9 ng/ml) with maximal occupancies of 106.8 +/- 8.3% across all brain regions. There is a weak correlation between oral sertraline and plasma sertraline. Occupancy measures vary based on the reference region and outcome measure used.


CONCLUSIONS
Occupancy studies and postmortem autoradiography can help define the optimal reference region. Reference tissue modeling using the optimal reference region returns the same occupancy measures as those determined using an arterial input function.
Parsey
Ramin V
RV
Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, New York, USA. rparsey@neuron.cpmc.columbia.edu
Kent
Justine M
JM
Oquendo
Maria A
MA
Richards
Misty C
MC
Pratap
Mali
M
Cooper
Thomas B
TB
Arango
Victoria
V
Mann
J John
JJ
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D001345:Autoradiography / Q000379:methods; D001596:Benzylamines / Q000493:pharmacokinetics*; D001921:Brain / Q000033:anatomy & histology / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism; D001931:Brain Mapping; D002247:Carbon Isotopes / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted / Q000379:methods; D007099:Imipramine / Q000493:pharmacokinetics; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008875:Middle Aged; D049268:Positron-Emission Tomography; D011180:Postmortem Changes; D012016:Reference Values; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D020280:Sertraline / Q000097:blood / Q000494:pharmacology*; D013997:Time Factors; D014018:Tissue Distribution / Q000187:drug effects; D014316:Tritium / Q000493:pharmacokinetics
D001596:Benzylamines; D002247:Carbon Isotopes; D007099:Imipramine; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D020280:Sertraline; D014316:Tritium; C420885:N,N-dimethyl-2-(2-amino-4-cyanophenylthio)benzylamine