Synthesis and evaluation of radiolabeled analogs of the antidepressant drug zimelidine as potential SPECT-ligands for the serotonin transporter.

Z-3-(4-bromophenyl)-N,N-dimethyl-3-(3-pyridinyl)-2-propen-1-amine or zimelidine (ZIM) and its first metabolite nor-zimelidine, were radioiodinated via a nonisotopic exchange, using the Cu(I)-assisted nucleophilic labeling method. To evaluate their potential as SPECT ligands for the serotonin transporter (SERT), the biodistribution of both ligands was determined and pretreatment "blocking" studies performed. Both radioligands demonstrated a good brain penetration of 0.8-1% ID/g, stable after 60 min., p.i., and a brain/blood ratio of up to 3. In vivo brain distribution did not reveal specific binding. Blocking studies by pretreatment with a known SERT ligand, had minor influence on the uptake of [(123)I]I-ZIM, between the several isolated brain regions. It may therefore be concluded that [(123)I]I-ZIM and [(123)I]I-nor-ZIM do not appear to be promising SPECT ligands for the SERT.

[The existence on the serotonin carrier of 2 independent sites for the specific binding of trazodone and imizin]. / O sushchestvovanii na serotoninovom perenoschike dvukh nezavisimykh mest spetsificheskogo sviazyvaniia trazodona i imizina.

A combined effect of zimelidine or trazodone on (3H)-serotonin uptake by the rat brain synaptosomes in the presence of 120 nM imipramine was studied. Imipramine and zimelidine were found to inhibit (3H)-serotonin uptake by a competitive manner, whereas trazodone was a noncompetitive inhibitor. Zimelidine, but not trazodone, was shown to bind to serotonin carrier at the same site as imipramine.

Stereoselective N-oxygenation of zimeldine and homozimeldine by the flavin-containing monooxygenase.

The metabolism of (Z)- and (E)-zimeldine and (Z)- and (E)-homozimeldine in hepatic rat and hog microsomes is described. The major metabolite observed in all cases examined was the tertiary amine N-oxide and it was formed at a rate 7-20 times that of norzimeldine or homonorzimeldine. N-Oxygenation requires NADPH and is stimulated by n-octylamine. Thiobenzamide and methimazole significantly inhibit N-oxide formation whereas heat pretreatment of microsomes completely abolishes N-oxide formation, strongly suggesting that zimeldine N-oxygenation if solely dependent on the flavin-containing monooxygenase. Hog liver microsomes N-oxygenate the Z-allylic and homoallylic tertiary amines in marked preference to the E-isomers, whereas rat liver microsomes N-oxygenate E-isomers to a greater extent than Z-isomers. Thus, opposite stereoselectivity for zimeldine N-oxygenation occurs in rat liver and hog liver microsomes.

Compliance among heavy alcohol users in clinical drug trials.

A high level of patient compliance is essential in determining the efficacy and safety of treatment with new drugs. Alcohol abusers are generally considered to exhibit a low level of compliance with respect to the taking of medication. This study describes a selection strategy and compares methods of determining compliance in two clinical trials assessing the effects of zimelidine and citalopram on ethanol intake in nondepressed male heavy drinkers (greater than 4 drinks/day). Objective methods included the use of a tracer substance (riboflavin), measurement of neurochemical effects (serotonin uptake inhibition), and measurement of drug and metabolite concentrations in body fluids (blood and urine). Other methods included self-report and pill count. Mean compliance estimates for the taking of medication ranged from 78 to 97% depending on the method used. Methods to determine ethanol use included daily self-monitoring and daily urine alcohol measurement. Alcohol consumption correlated with urine alcohol measurement (r = 0.62, p less than .001). These comprehensive assessments of compliance allowed accurate evaluations of drug efficacy and toxicity. The study demonstrates that with stringent selection and reinforcement procedures, exceptionally high levels of compliance can be attained in this group of subjects. Similar procedures should be included in trials evaluating new drugs.