A novel serotonin transporter ligand: (5-iodo-2-(2-dimethylaminomethylphenoxy)-benzyl alcohol

The serotonin transporters (SERT) are the primary binding sites for selecti ve serotonin reuptake inhibitors, commonly used antidepressants such as flu oxetine, sertraline, and paroxetine. Imaging of SERT with positron emission tomography and single photon emission computed tomography in humans would provide a useful tool for understanding how alterations of this system are related to depressive illnesses and other psychiatric disorders. In this ar ticle the synthesis and characterization of [I-125]ODAM [(5-iodo-2-( 2-dime thylaminomethylphenoxy)-benzyl alcohol, 9)] as an imaging agent in the eval uation of central nervous system SERT are reported. A new reaction scheme w as developed for the preparation of compound 9, ODAM, and the corresponding tri-n-butyltin derivative 10. Upon reacting 10 with hydrogen peroxide and sodium[I-125]iodide, the radiolabeled [I-125]9 was Obtained in good yield ( 94% yield, radiochemical purity >95%). In an initial binding study using co rtical membrane homogenates of rat brain, ODAM displayed a good binding aff inity with a value of K-i = 2.8 +/- 0.88 nM. Using LLC-PK1 cells specifical ly expressing the individual transporter (i.e. dopamine [DAT], norepinephri ne [NET], and SERT, respectively), ODAM showed a strong inhibition on SERT (K-i = 0.12 +/- 0.02 nM). Inhibition constants for the other two transporte rs were lower (K-i = 3.9 +/- 0.7 mu M and 20.0 +/- 1.9 nM for DAT and NET, respectively). Initial biodistribution study in rats after an intravenous ( IV) injection of [I-125]ODAM showed a rapid brain uptake and washout (2.03, 1.49, 0.79, 0.27, and 0.07% dose/organ at 2, 30, 60, 120, and 240 min, res pectively). The hypothalamus region where the serotonin neurons are located exhibited a high specific uptake. Ratios of hypothalamus-cerebellum/cerebe llum based on percent dose per gram of these two regions showed values of 0 .35, 0.86, 0.86, 0.63, and 0.34 at 2, 30, 60, 120, and 240 min, post-IV inj ection, respectively. The specific uptake in hypothalamus can be effectivel y blocked by pretreatment of known SERT ligands. The results suggest that t his novel ligand displays desirable in vitro and in vivo properties as a po tential SERT imaging agent. NUCL MED BIOL 27;2:169-175, 2000. 9 (C) 2000 El sevier Science Inc. All rights reserved.