Novel radiotracers for imaging the serotonin transporter by positron emission tomography: synthesis, radiosynthesis, and in vitro and ex vivo evaluation of (11)C-labeled 2-(phenylthio)araalkylamines.
A series of four 2-(phenylthio)araalkylamines have been radiolabeled with (11)C and evaluated as potential radiotracers for imaging the serotonin transporter (SERT) by positron emission tomography (PET). All four candidates display high affinity for SERT and low affinity for the dopamine or norepinephrine transporters using in vitro binding assays. Biodistribution studies in rats demonstrated that tail-vein injection of the (11)C-labeled radiotracers resulted in high brain uptake of radioactivity with a preferential distribution in brain regions known to be rich in SERT such as hypothalamus and thalamus. The most promising candidate, 16, had hypothalamus-to-cerebellum ratios of 9:1, 1 h postinjection, an indication of high specific to nonspecific binding. Ex vivo pharmacological studies demonstrated that uptake in SERT-rich brain regions was both saturable and selective for SERT. Two of the tested radiotracers, 15 and 16, have highly favorable properties for imaging SERT and will be used in pilot human PET imaging studies.
Wilson
A A
AA
PET Centre, Centre for Addiction and Mental Health, and Department of Psychiatry, University of Toronto, Toronto, Ontario M5T 1R8, Canada. aaw@camhpet.on.ca
Ginovart
N
N
Schmidt
M
M
Meyer
J H
JH
Threlkeld
P G
PG
Houle
S
S
D000814:Aniline Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D002250:Carbon Radioisotopes; D002352:Carrier Proteins / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007553:Isotope Labeling; D008024:Ligands; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D026901:Membrane Transport Proteins; D008566:Membranes; D009419:Nerve Tissue Proteins; D011485:Protein Binding; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism*; D018490:Serotonin Agents / Q000633:toxicity; D050486:Serotonin Plasma Membrane Transport Proteins; D013329:Structure-Activity Relationship; D013440:Sulfides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D014055:Tomography, Emission-Computed; D010133:p-Chloroamphetamine / Q000633:toxicity
C412821:2-(2-dimethylaminomethylphenylsulfanyl)-5-methoxyphenylamine; C412822:3-amino-4-(2-dimethylaminomethylphenylsulfanyl)benzonitrile; D000814:Aniline Compounds; D002250:Carbon Radioisotopes; D002352:Carrier Proteins; D008024:Ligands; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D019275:Radiopharmaceuticals; C493230:SLC6A4 protein, human; D018490:Serotonin Agents; D050486:Serotonin Plasma Membrane Transport Proteins; C493232:Slc6a4 protein, rat; D013440:Sulfides; D012701:Serotonin; D010133:p-Chloroamphetamine