5-Chloro-2-(2′-((dimethylamino)methyl)-4′-iodophenylthio)benzenamine: a new serotonin transporter ligand

Abstract

Two novel ligands with a 4′-substitution on the phenyl ring B of biphenylthiol: 5-chloro-2-(2′-((dimethylamino)methyl)-4′-iodophenylthio)benzenamine, 7, and 2-(2′-((dimethylamino) methyl)-4′-methoxyphenylthio)-5-iodobenzenamine, 8, were prepared and tested as potential serotonin transporter (SERT) imaging agents. The new ligands displayed extremely high binding affinities to SERT (K i = 0.22 ± 0.09 and 0.11 ± 0.04 nM, respectively), with very low binding affinities to dopamine and norepinephrine transporters (K i > 1, 000 nM). The corresponding [ 125 I]7 and [ 125 I] 8 were successfully prepared from the tri-n-butyltin derivatives. They showed good brain uptakes and prolonged retention after iv injection in rats (brain uptake was 1.77 and 0.98 %dose/g for [ 125 I] 7 and 0.92 and 0.29 %dose/g for [ 125 I]8 at 2 and 120 minutes, respectively). Significantly, [ 125 I]7 showed excellent uptake and prolonged retention in the hypothalamus, where the SERT concentration is the highest. The hypothalamus/cerebellum ratios (target to background ratios) were 4.24, 7.10, 8.24 and 12.6 at 2, 4, 6 and 12 hours, respectively. The hypothalamus/cerebellum ratios for [ 125 I]8 were 3.97, 5.57 and 5.06 at 1, 2 and 4 hours, respectively. Adding the 4′-iodo-group to the phenyl ring B of 7 appeared to reduce the rate of clearance from the brain, and the kinetics favored uptake and retention in the hypothalamus. The localization of [ 125 I]7 in the hypothalamus region in the brain of rats could be blocked by pretreatment with (+)McN5652, escitalopram and ADAM (2), all selective serotonin transporter ligands (at 2 mg/Kg dose, iv, 5 min pretreatment). Ex vivo autoradiograms of rat brain sections (at 4 hr after iv injection of [ 125 I]7) showed intense labeling in regions of the brain known to have high SERT density. The excellent selective uptake and retention in the hypothalamus region suggests that [ 123 I]7 is a potential lead compound for developing new imaging agents targeting SERT binding sites with single photon emission computed tomography (SPECT).

(R)-N-Methyl-3-(3-125I-pyridin-2-yloxy)-3-phenylpropan-1-amine: a novel probe for norepinephrine transporters

“…These cells are grown and maintained in our laboratory providing a convenient source of specific DAT, SERT or NET protein for in vitro binding assays. Because it is easy, readily available and provides comparable data for in vitro binding assays, our lab has used the cells expressing the specific transporter instead of membrane homogenates of rat frontal cortex or striatum to screen monoamine transporter inhibitors [29]. The compounds 8-11 synthesized and reported in this paper were subjected to binding evaluations for the monoamine transporters NET, SERT and DAT.…”

2-(2′-((Dimethylamino)methyl)-4′-(fluoroalkoxy)-phenylthio)benzenamine Derivatives as Serotonin Transporter Imaging Agents

“…A wealth of information on the synthesis of biphenylthiols (1)(2)(3)(4)(5) has been reported in the past few years. 27,28,[30][31][32][33]45,46 The new series of biphenylthiols 28-42 were successfully prepared using schemes 1-3. The synthesis of fluorinated biphenylthiols 28-31 is illustrated in scheme 1.…”

“…Alternatively, the above mixture was irradiated with microwaves at 150°C for 15 min followed by the work-up described earlier gave the desired product. (32) was prepared from 20 as a yellow oil in 87% yield according to general procedure F. 1 (33) was prepared from 21 as a yellow oil in 85% yield according to general procedure F. 1 (34) was prepared from 23 as a yellow oil in 70% yield according to general procedure F. 1 (45) was prepared from 20 as a yellow oil in 94% yield according to general procedure F. 1 (46) was prepared from 21 as a yellow oil in 93% yield according to general procedure F. 1 General Procedure (G) for Selective Reduction of Amide Group-To a solution of amides (45-52 and 32-34) (0.18 mmol) in THF (10 mL) at 0°C, 1.0 M BH 3 -THF (5 eqiuivalent) was added. The mixture was heated to reflux for 1.5-2 hrs.…”

Synthesis and in vitro evaluation of new diphenyl ether derivatives as serotonin transporter ligands

“…Therefore, it seems that the introduction of a fluorine atom at R 3 position and substitution of the sulphur by an oxygen in the diphenyl bridge has almost no effect on the affinities, which is in accordance with the reported literature [35] . Moreover, Oya et al [36] showed that compounds with a O(CH 2 ) 2 F, OMe, Br, I, or OH function at R 3 position also displayed high SERT affinities. Therefore, the introduction of a halogen at this part of the molecule does not affect the SERT affinity of the ligands, and the replacement of the halogen atom by a OH, OMe, or O(CH 2 ) 2 F group also affords compounds with nanoto subnanomolar affinities.…”