Synthesis and in vivo evaluation of fluorine-18 and iodine-123 labeled 2beta-carbo(2-fluoroethoxy)-3beta-(4'-((Z)-2-iodoethenyl)phenyl)nortropane as a candidate serotonin transporter imaging agent.
2Beta-carbo(2-fluoroethoxy)-3beta-(4'-((Z)-2-iodoethenyl)phenyl)nortropane (betaFEpZIENT, 1) was synthesized as a serotonin transporter (SERT) imaging agent for both positron emission tomography (PET) and single photon emission computerized tomography (SPECT). The binding affinity of 1 to human monoamine transporters showed a high affinity for the SERT (Ki = 0.08 nM) with respect to the dopamine transporter (DAT) (Ki = 13 nM) and the norepinephrine transporter (NET) (Ki = 28 nM). In vivo biodistribution and blocking studies performed in male rats demonstrated that [123I]1 was selective and specific for SERT. In vivo microPET brain imaging studies in an anesthetized monkey with [18F]1 showed high uptake in the diencephalon and brainstem with peak uptake achieved at 120 min. A chase study with (R,S)-citalopram.HBr displaced [18F]1 radioactivity from all SERT-rich brain regions. A chase study with the DAT ligand 2beta-carbophenoxy-3beta-(4-chlorophenyl)tropane (9, RTI-113) failed to displace [18F]1, indicating that [18F]1 is specific to the SERT. The in vivo evaluation of [18F]1 indicates that this radiotracer is a good candidate for mapping and quantifying CNS SERT.
Plisson
Christophe
C
Department of Radiology, Emory University, Atlanta, Georgia, USA.
Stehouwer
Jeffrey S
JS
Voll
Ronald J
RJ
Howell
Leonard
L
Votaw
John R
JR
Owens
Michael J
MJ
Goodman
Mark M
MM
D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D005462:Fluorine Radioisotopes; D006801:Humans; D007457:Iodine Radioisotopes; D007553:Isotope Labeling; D008253:Macaca mulatta; D008297:Male; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism; D009662:Nortropanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D013237:Stereoisomerism; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon
C523624:2-carbo(2-fluoroethoxy)-3-(4'-(2-iodoethenyl)phenyl)nortropane; D050483:Dopamine Plasma Membrane Transport Proteins; D005462:Fluorine Radioisotopes; D007457:Iodine Radioisotopes; D050484:Norepinephrine Plasma Membrane Transport Proteins; D009662:Nortropanes; D019275:Radiopharmaceuticals; D050486:Serotonin Plasma Membrane Transport Proteins