Synthesis and characterization of iodine-123 labeled 2beta-carbomethoxy-3beta-(4'-((Z)-2-iodoethenyl)phenyl)nortropane. A ligand for in vivo imaging of serotonin transporters by single-photon-emission tomography.
2beta-Carbomethoxy-3beta-(4'-((Z)-2-iodoethenyl)phenyl)nortropane (ZIENT) (6) and 2beta-carbomethoxy-3beta-(4'-((E)-2-iodoethenyl)phenyl)nortropane (EIENT) (10) were prepared and evaluated in vitro and in vivo for serotonin transporter (SERT) selectivity and specificity. High specific activity [(123)I]ZIENT and [(123)I]EIENT were synthesized in 45% (n = 5) and 42% (n = 4) radiochemical yield (decay-corrected to end of bombardment (EOB)), respectively, by preparation of the precursor carbomethoxy-3beta-(4'-((Z)-2-trimethylstannylethenyl)phenyl)nortropane (7) and 2beta-carbomethoxy-3beta-(4'-((E)-2-tributylstannylethenyl)phenyl)nortropane (9), respectively, followed by treatment with no carrier-added sodium [(123)I]iodide and hydrogen peroxide in ethanolic HCl. Competition binding in cells stably expressing the transfected human SERT, dopamine transporter (DAT), and norepinephrine transporter (NET) using [(3)H]citalopram, [(3)H]WIN 35,428, and [(3)H]nisoxetine, respectively, demonstrated the following order of SERT affinity (K(i) in nM): ZIENT (0.05) > nor-CIT (0.12) >> EIENT (1.15) > fluvoxamine (1.46). The affinity of ZIENT and EIENT for DAT was 69 and 1.6-fold lower, respectively, than for SERT. In vivo biodistribution and blocking studies were performed in male rats and demonstrated that the brain uptake of [(123)I]ZIENT was selective and specific for SERT-rich regions (hypothalamus, striatum, pons, and prefrontal cortex). SPECT brain imaging studies in monkeys demonstrated high [(123)I]ZIENT uptake in the diencephalon, which resulted in diencephalon-to-cerebellum ratios of 2.12 at 190 min. [(123)I]ZIENT uptake in the diencephalon achieved transient equilibrium at 157 min. In a displacement experiment of [(123)I]ZIENT in a cynomolgus monkey, radioactivity was reduced by 39% in the diencephalon at 101 min following injection of citalopram. The high specific activity one-step radiolabeling preparation and high selectivity of [(123)I]ZIENT for SERT support its candidacy as a radioligand for mapping brain SERT sites.
Goodman
Mark M
MM
Department of Radiology, Emory University, Atlanta, Georgia 30320, USA. mgoodma@emory.edu
Chen
Ping
P
Plisson
Christophe
C
Martarello
Laurent
L
Galt
James
J
Votaw
John R
JR
Kilts
Clinton D
CD
Malveaux
Gene
G
Camp
Vernon M
VM
Shi
Bing
B
Ely
Timothy D
TD
Howell
Leonard
L
McConathy
Jon
J
Nemeroff
Charles B
CB
D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D005260:Female; D006367:HeLa Cells; D006801:Humans; D007457:Iodine Radioisotopes; D007553:Isotope Labeling; D008024:Ligands; D008252:Macaca fascicularis; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D009662:Nortropanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D011869:Radioligand Assay; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon
C472792:2-carbomethoxy-3-(4'-(2-iodoethenyl)phenyl)nortropane; D002352:Carrier Proteins; D007457:Iodine Radioisotopes; D008024:Ligands; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D009662:Nortropanes; D019275:Radiopharmaceuticals; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; C493232:Slc6a4 protein, rat; D012701:Serotonin