Synthesis, radiosynthesis, and biological evaluation of fluorine-18-labeled 2beta-carbo(fluoroalkoxy)-3beta-(3'-((Z)-2-haloethenyl)phenyl)nortropanes: candidate radioligands for in vivo imaging of the serotonin transporter with positron emission tomography.
The meta-vinylhalide fluoroalkyl ester nortropanes 1-4 were synthesized as ligands of the serotonin transporter (SERT) for use as positron emission tomography (PET) imaging agents. In vitro competition binding assays demonstrated that 1-4 have a high affinity for the SERT (K(i) values = 0.3-0.4 nM) and are selective for the SERT over the dopamine and norepinephrine transporters (DAT and NET). MicroPET imaging in anesthetized cynomolgus monkeys with [(18)F]1-[(18)F]4 demonstrated that all four tracers behave similarly with peak uptake in the SERT-rich brain regions achieved after 45-55 min, followed by a steady washout. An awake monkey study was performed with [(18)F]1, which demonstrated that the uptake of [(18)F]1 was not influenced by anesthesia. Chase studies with the SERT ligand 15 displaced [(18)F]1-[(18)F]4, but chase studies with the DAT ligand 16 did not displace [(18)F]1-[(18)F]4 thus indicating that the tracers were binding specifically to the SERT.
Stehouwer
Jeffrey S
JS
Department of Radiology, Emory University, Atlanta, GA, USA.
Jarkas
Nachwa
N
Zeng
Fanxing
F
Voll
Ronald J
RJ
Williams
Larry
L
Camp
Vernon M
VM
Malveaux
Eugene J
EJ
Votaw
John R
JR
Howell
Leonard
L
Owens
Michael J
MJ
Goodman
Mark M
MM
D000818:Animals; D015195:Drug Design; D005462:Fluorine Radioisotopes / Q000737:chemistry*; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008253:Macaca mulatta; D008956:Models, Chemical; D018377:Neurotransmitter Agents / Q000737:chemistry; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism; D009662:Nortropanes / Q000138:chemical synthesis* / Q000737:chemistry*; D049268:Positron-Emission Tomography / Q000295:instrumentation / Q000379:methods*; D019275:Radiopharmaceuticals / Q000737:chemistry; D050486:Serotonin Plasma Membrane Transport Proteins / Q000737:chemistry*; D013997:Time Factors
D005462:Fluorine Radioisotopes; D008024:Ligands; D018377:Neurotransmitter Agents; D050484:Norepinephrine Plasma Membrane Transport Proteins; D009662:Nortropanes; D019275:Radiopharmaceuticals; D050486:Serotonin Plasma Membrane Transport Proteins