Synthesis of 4'-iodo-5-methoxy-valerophenone O-(2-aminoethyl)oxime as an agent for exploration of serotoninergic transporter.
The serotonin reuptake process is observed in the central nervous system and in cells derived from the neural crest. It would therefore be of great interest to visualize this reuptake for brain exploration and to visualize the tumors derived from these cells (Apudome). Fluvoxamine has been described as a specific uptake inhibitor for serotonin uptake and we therefore supposed that an iodinated derivative of this compound would be a suitable tracer for this purpose. We had shown by computer-assisted investigation that the trifluoromethyl group of fluvoxamine can be replaced by iodine without changing the steric hindrance of the structure. We therefore expected that this result would allow the development of a new iodinated ligand for human exploration by SPECT which would inhibit for the serotoninergic transporter. This new ligand is 4'-iodo-5-methoxyvalerophenone O-(2-aminoethyl)oxime in its E configuration. In vitro binding studies demonstrated that this iodinated ligand has a weaker affinity for the serotonin uptake sites than fluvoxamine. Steric hindrance is not sufficient to predict affinity, other structural factors such as electronic density and dipole moment must be considered to explain the biological difference between fluvoxamine and its iodinated analog.
Branger
C
C
INSERM U316, Université François Rabelais, Faculté des Sciences Pharmaceutiques, Tours, France.
Garreau
L
L
Dognon
A M
AM
Frangin
Y
Y
Caillet
M
M
Ombetta-Goka
J E
JE
Chalon
S
S
Besnard
J C
JC
Guilloteau
D
D
D000818:Animals; D002352:Carrier Proteins / Q000032:analysis / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism; D016666:Fluvoxamine; D006801:Humans; D007202:Indicators and Reagents; D007457:Iodine Radioisotopes; D009682:Magnetic Resonance Spectroscopy; D008562:Membrane Glycoproteins / Q000032:analysis / Q000378:metabolism*; D026901:Membrane Transport Proteins; D008958:Models, Molecular; D008968:Molecular Conformation; D009419:Nerve Tissue Proteins; D010091:Oximes / Q000138:chemical synthesis* / Q000378:metabolism; D051381:Rats; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins; D013055:Spectrophotometry, Infrared; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods
C093926:4'-iodo-5-methoxyvalerophenone-O-(2-aminoethyl)oxime; D002352:Carrier Proteins; D007202:Indicators and Reagents; D007457:Iodine Radioisotopes; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D010091:Oximes; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; C493232:Slc6a4 protein, rat; D012701:Serotonin; D016666:Fluvoxamine