Isotopic effect study of propofol deuteration on the metabolism, activity, and toxicity of the anesthetic.

The use of isotopic substitution to delay the oxidative metabolism of the anesthetic propofol 1 was studied. The aromatic hydrogens of propofol 1 were replaced by deuterium to produce the mono- and trideuterated derivatives 4 and 5. In vitro metabolic studies on human hepatic microsomes showed no isotopic effect in the para hydroxylation of propofol, and 1, 4, and 5 display similar hypnotic activity and toxicity in mice.

Synthesis of tropane and nortropane analogues with phenyl substitutions as serotonin transporter ligands.

The effects of structural modifications of 2 beta-carbomethoxy-3 beta-phenyl tropane analogues were evaluated on in vitro affinity to the dopamine (DAT) and serotonin (5-HTT) transporters in rat brain tissue. The introduction of a large alkyl group at the 4'-position of the phenyl ring, affording 2 beta-carbomethoxy-3 beta-(4'-alkylphenyl) tropane, diminished the affinity for the DAT whereas moderate 5-HTT affinity was obtained. The introduction of an iodine at the 3'-position of the 4'-alkylphenyl, affording 2 beta-carbomethoxy-3 beta-(3'-iodo-4'-alkylphenyl) tropane, and N-demethylation, affording 2 beta-carbomethoxy-3 beta-(3'-iodo-4'-alkylphenyl) nortropane, improved affinity and specificity for the 5-HTT. It could be assumed from these results that the combination of these three modifications of tropane structure yielded highly selective compounds for the 5-HTT. Of the new compounds synthesized, the most selective cocaine derivative, 2 beta-carbomethoxy-3 beta-(3'-iodo-4'-isopropylphenyl) nortropane (8d) labeled with iodine-123 or carbon-11, could be a potential ligand for exploration of the 5-HT transporter by SPET or PET.

PET examination of three potent cocaine derivatives as specific radioligands for the serotonin transporter.

Several positron emission tomography (PET) radioligands based on the aryl tropane structure have been used for studies on monoamine reuptake sites. RTI-364, RTI-330, and RTI-357 (3-beta-(4'-n-propyl-,4'-iso-propyl-, and 4'-iso-propenyl-phenyl)nortropane-2-beta-carboxylic acid methyl ester) are three recently synthesized cocaine analogues with higher affinity for the serotonin (5-HTT) than the dopamine transporter (DAT). Unlabelled RTI-364 and RTI-330 were prepared in a two-step synthesis. The key step was the addition of the appropriate propyl Grignard reagent to anhydroecgonine methyl ester. RTI-357 was prepared in a three-step synthesis with a palladium-catalyzed coupling reaction of beta-CIT and isopropenylzinc bromide as key step. Hydrolysis of the ester functions gave the carboxylic acid analogues of RTI-364, RTI-330, and RTI-357, which were labelled with 11C using [11C]methyl iodide in dimethyl formamide (DMF) and tetrabutylammonium hydroxide (TBAH) as base. All three compounds entered the monkey brain in a high degree (approximately 5-10%). There was a low uptake of [11C]RTI-364 in serotonin-rich brain areas, whereas [11C]RTI-330 and [11C]RTI-357 showed a marked uptake of radioactivity in the thalamus and the brainstem, regions known to contain serotonin transporters. Transient equilibrium was reached at 15 and 40 min for [11C]RTI-330 and [11C]RTI-357, respectively. After pretreatment with citalopram, the ratio of radioactivity in the thalamus and the brainstem to the cerebellum were markedly reduced for [11C]RTI-357 but not for [11C]RTI-330. The results indicate that [11C]RTI-357 is a potential PET radioligand for quantitation of the serotonin reuptake site.

A selective radiobrominated cocaine analogue for imaging of dopamine uptake sites: pharmacological evaluation and PET experiments.

(E)-N-(3-bromoprop-2-enyl)-2beta-carbomethoxy-3beta-4'-tolyl -nortropane or PE2Br, an analogue of cocaine was labelled with the positron emitter 76Br (T1/2=16 h) for pharmacological evaluation in the rat and PET investigation in the monkey. [76Br]PE2Br was obtained by electrophilic substitution from the tributylstannyl precursor with radiochemical yield of 80%. In vivo biodistribution studies of [76Br]PE2Br (20 MBq/nmol) in rats showed a high uptake in the striatum (2.2% ID/g tissue at 15 min p.i.). The striatum to cerebellum radioactivity ratio was 6 at 1 hour p.i. Striatal uptake of [76Br]PE2Br was almost completely prevented by pretreatment with GBR 12909, but citalopram and maprotiline had no effect, confirming the selectivity of the radioligand for the dopamine transporter. PET imaging of the biodistribution of [76Br]PE2Br in the baboon demonstrated rapid and high uptake in the brain (5% ID at 3 min p.i.). The striatal radioactivity concentration reached a plateau at 20 min p.i. (7% ID/100 mL). The uptake in the cortex and cerebellum was very low. A significantly higher uptake in the thalamus was observed. At 1h p.i., the striatum to cerebellum ratio and thalamus to cerebellum ratio were 8 and 1.9 respectively. In competition experiments the radioactivity in the striatum and the thalamus was displaced by 5 mg/kgof cocaine and 5 mg/kg of GBR 12909, but citalopram and maprotiline had no effect. These results showed that [76Br]PE2Br is in vivo a potent and selective radioligand suitable for PET imagingof the dopamine transporter.