Neuroimaging of the serotonin reuptake site requires high-affinity ligands.
Numerous attempts have been made to develop suitable radiolabeled tracers for positron emission tomography or single photon emission computed tomography imaging of the serotonin transporter (SERT), but most often, negative outcomes are reported. The aim of this study is to define characteristics of a good SERT radioligand and to investigate species differences. We examined seven different selective serotonin reuptake inhibitors (SSRIs) and that except for one all have been previously tested as emission tomography ligands. The outcome of the ligands as emission tomography tracers was compared in relation with receptor density (Bmax) and/or ligand affinity (Kd) in rat and monkey cerebrum and cerebellum (reference region) membranes. [3H]-(S)-Citalopram and [3H]-(+)-McN5652 display statistically significantly lower affinity, whereas [3H]paroxetine displays statistically significantly higher affinity for SERT in monkey cortex when compared with the rat cerebrum. The affinity of [3H]MADAM, [123I]ADAM, and [11C]DASB for SERT obtained with rat cerebrum and monkey cortex are similar. In monkey cortex, Kd and Bmax could not be determined with [3H]fluoxetine. Of the seven SSRIs, [3H]-(S)-citalopram, [3H]MADAM, and [11C]DASB displayed significant specific binding to SERT in monkey cerebellum, with Bmax cortex:cerebellum ratios being 17, 3, and 4, respectively. In rat brain tissue the ratios were 12, 6, and 3, respectively. In conclusion, it can be estimated that imaging of the human SERT in a high-density region requires radioligands with Kd values between 0.03 and a maximum of 0.3 nM (at 37 degrees C). The differential specific cerebellar binding raises the question of the suitability of cerebellum as a reference region for nonspecific binding.
Neurobiology Research Unit N9201, Rigshospitalet, University Hospital Copenhagen, DK-2100 Copenhagen, Denmark. bef@psykiatri.aaa.dk
Betina
B
Elfving
Jacob
J
Madsen
Gitte M
GM
Knudsen
D000818:Animals; D001596:Benzylamines / Q000493:pharmacokinetics; D001665:Binding Sites; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism*; D015283:Citalopram / Q000493:pharmacokinetics; D007546:Isoquinolines / Q000493:pharmacokinetics; D007554:Isotopes / Q000493:pharmacokinetics; D008253:Macaca mulatta; D008297:Male; D011877:Radionuclide Imaging; D051381:Rats; D017208:Rats, Wistar; D012702:Serotonin Antagonists / Q000493:pharmacokinetics; D017367:Selective Serotonin Reuptake Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D014018:Tissue Distribution
D001596:Benzylamines; D015283:Citalopram; D007546:Isoquinolines; D007554:Isotopes; D012702:Serotonin Antagonists; D017367:Selective Serotonin Reuptake Inhibitors; C470437:N,N-dimethyl-2-(2-amino-4-methylphenylthio)benzylamine; C058079:McN 5652