Synthesis, radiosynthesis, and biological evaluation of carbon-11 labeled 2beta-carbomethoxy-3beta-(3'-((Z)-2-haloethenyl)phenyl)nortropanes: candidate radioligands for in vivo imaging of the serotonin transporter with positron emission tomography.
2beta-carbomethoxy-3beta-(3'-((Z)-2-iodoethenyl)phenyl)nortropane (mZIENT, 1) and 2beta-carbomethoxy-3beta-(3'-((Z)-2-bromoethenyl)phenyl)nortropane (mZBrENT, 2) were synthesized and evaluated for binding to the human serotonin, dopamine, and norepinephrine transporters (SERT, DAT, and NET, respectively) using transfected cells. Both 1 and 2 have a high affinity for the SERT (Ki=0.2 nM) and are approximately 160 times more selective for the SERT than the DAT. Compound 2 has a significantly higher affinity for the NET than 1, and this may be a result of the different size and electronegativity of the halogen atoms. MicroPET imaging in nonhuman primates with [11C]1 and [11C]2 demonstrated that both tracers behave similarly in vivo with high uptake being observed in the SERT-rich brain regions and peak uptake being achieved in about 55 min postinjection. Chase studies with citalopram and methylphenidate demonstrated that this uptake is the result of preferential binding to the SERT.
Stehouwer
Jeffrey S
JS
Department of Radiology, Emory University, Atlanta, Georgia 30322, USA.
Jarkas
Nachwa
N
Zeng
Fanxing
F
Voll
Ronald J
RJ
Williams
Larry
L
Owens
Michael J
MJ
Votaw
John R
JR
Goodman
Mark M
MM
D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D002250:Carbon Radioisotopes; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D006801:Humans; D007553:Isotope Labeling; D008024:Ligands; D008252:Macaca fascicularis; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism; D009662:Nortropanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D049268:Positron-Emission Tomography; D011869:Radioligand Assay; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C516222:2-carbomethoxy-3-(3'-(2-bromoethenyl)phenyl)nortropane; C516221:2-carbomethoxy-3-(3'-(2-iodoethenyl)phenyl)nortropane; D002250:Carbon Radioisotopes; D050483:Dopamine Plasma Membrane Transport Proteins; D008024:Ligands; D050484:Norepinephrine Plasma Membrane Transport Proteins; D009662:Nortropanes; D019275:Radiopharmaceuticals; D050486:Serotonin Plasma Membrane Transport Proteins