(3S)-3-(2,3-difluorophenyl)-3-methoxypyrrolidine (IRL752) -a Novel Cortical-Preferring Catecholamine Transmission- and Cognition-Promoting Agent.

Here we describe for the first time the distinctive pharmacological profile for (3S)-3-(2,3-difluorophenyl)-3-methoxypyrrolidine (IRL752), a new phenyl-pyrrolidine derivative with regioselective central nervous system transmission-enhancing properties. IRL752 (3.7-150 µmol/kg, s.c.) was characterized through extensive in vivo studies using behavioral, tissue neurochemical, and gene expression as well as microdialysis methods. Behaviorally, the compound normalized tetrabenazine-induced hypoactivity, whereas it was unable to stimulate basal locomotion in normal animals or either accentuate or reverse hyperactivity induced by amphetamine or MK-801. IRL752 induced but minor changes in monoaminergic tissue neurochemistry across noradrenaline (NA)- and dopamine (DA)-dominated brain regions. The expression of neuronal activity-, plasticity-, and cognition-related immediate early genes (IEGs), however, increased by 1.5-fold to 2-fold. Furthermore, IRL752 dose-dependently enhanced cortical catecholamine dialysate output to 600%-750% above baseline, whereas striatal DA remained unaltered, and NA rose to ∼250%; cortical and hippocampal dialysate acetylcholine (ACh) increased to ∼250% and 190% above corresponding baseline, respectively. In line with this cortically preferential transmission-promoting action, the drug was also procognitive in the novel object recognition and reversal learning tests. In vitro neurotarget affinity and functional data coupled to drug exposure support the hypothesis that 5-hydroxytryptamine 7 receptor and α2(C)-adrenoceptor antagonism are key contributors to the in vivo efficacy and original profile of IRL752. The cortical-preferring facilitatory impact on catecholamine (and ACh) neurotransmission, along with effects on IEG expression and cognition-enhancing features, are in line with the potential clinical usefulness of IRL752 in conditions wherein these aspects may be dysregulated, such as in axial motor and cognitive deficits in Parkinson disease. SIGNIFICANCE STATEMENT: This report describes the distinctive preclinical profile of (3S)-3-(2,3-difluorophenyl)-3-methoxypyrrolidine (IRL752). Its in vivo neurochemical, behavioral, microdialysis, and gene expression properties are consistent with a cortically regioselective facilitatory impact on catecholaminergic and cholinergic neurotransmission accompanied by cognitive impairment-reversing features. The pharmacological characteristics of IRL752 are in line with the clinical usefulness of IRL752 in conditions wherein these aspects may be dysregulated, such as in axial motor and cognitive deficits in Parkinson disease.

The dopaminergic stabilizer pridopidine is to a major extent N-depropylated by CYP2D6 in humans.

PURPOSE: The influence of the cytochrome P450 enzyme CYP2D6 in the metabolism of the novel dopaminergic stabilizer pridopidine was investigated in healthy Swedish Caucasians. METHODS: Six extensive metabolizers (EM) and six poor metabolizers (PM) of debrisoquine were given a single oral dose of pridopidine (EM, 50 mg; PM, 25 mg). RESULTS: The mean total plasma clearance of pridopidine was 541 and 138 mL/min in EM and PM, respectively (p = 0.003), and was slightly higher in PM than the mean renal plasma clearance (105 mL/min; p = 0.11). The mean plasma area under the time-concentration curve between time zero and 32 h (AUC(0-32 h)) of the N-depropyl metabolite ACR30 was higher in EM than in PM (1,377 vs. 61 nmol h/mL, respectively; p < 0.001). The urinary excretion of pridopidine + ACR30 was high in both EM (85 %) and PM (78 %). The dose-adjusted peak concentration (C(max)) was not statistically different in EM and PM; consequently, the oral absorption of pridopidine was close to complete. CONCLUSIONS: Following a single dose of pridopidine, the drug is N-depropylated by CYP2D6 in EM, while in PM the most important elimination pathway is renal glomerular filtration. Results of studies examining the effects of multiple repeat dosing suggest that the CYP2D6 enzyme is at least partly inactivated by pridopidine.

PNU-96391A (OSU6162) antagonizes the development of behavioral sensitization induced by dopamine agonists in a rat model for Parkinson's disease.

PNU-96391A is a weak dopamine (DA) D(2) receptor antagonist with behavioral stabilizing properties. Previous experiments revealed that PNU-96391A antagonizes the expression of L-DOPA induced behavioral sensitization (dyskinesias) in lesioned primates without inducing akinesia or reducing the anti-Parkinsonian efficacy of L-DOPA. This study evaluated the ability of PNU-96391A to block the development of DA agonist-induced behavioral sensitization in rats with unilateral 6-OH-DA lesions of the median forebrain bundle. Repeated twice daily treatment with L-DOPA and the decarboxylase inhibitor benserazide (15 and 5 mg/kg, IP, respectively), or quinpirole (D(2)/D(3) agonist, 0.1 mg/kg, SC) increased the contralateral rotations measured on day 7 and 14 as compared to day 1. PNU-96391A (10-60 mg/kg, SC, bid.) antagonized the development of behavioral sensitization induced by both agonists. The basal activity of L-DOPA was not affected while a reduction of quinpirole-induced rotations was observed after 30-60 mg/kg, SC of PNU-96391A. Neurochemical analyses confirmed >99 % reductions of striatal DA levels, unilaterally. Concomitant treatment with PNU-96391A and L-DOPA did not affect plasma levels of PNU-96391A indicating that the effects observed are not related to pharmacokinetic interactions. These results suggest that PNU-96391A could be therapeutically useful to prevent the development of behavioral sensitization induced by DA agonists.

Coadministration of (-)-OSU6162 with l-DOPA normalizes preproenkephalin mRNA expression in the sensorimotor striatum of primates with unilateral 6-OHDA lesions.

The substituted phenylpiperidine (-)-OSU6162 is a novel modulator of the dopaminergic systems with low affinity for dopamine D(2) receptors and potent normalizing effects on l-DOPA-induced dyskinesias. We studied the effects of coadministration of (-)-OSU6162 with l-DOPA on the regulation of striatal preproenkephalin (PPE) and prodynorphin (PDyn) mRNA expression in the primate brain by in situ hybridization histochemistry. Common marmoset monkeys sustaining unilateral 6-hydroxydopamine lesions of the nigrostriatal pathway received l-DOPA/carbidopa, l-DOPA/carbidopa plus (-)-OSU6162, or vehicle over 14 days. In vehicle-treated animals, PPE mRNA levels were markedly increased in the sensorimotor territory of the lesioned striatum. By contrast, a rather uniform lesion-induced reduction of PDyn mRNA levels was found in the vehicle group. Subchronic l-DOPA treatment induced a further increase in PPE mRNA expression in a number of sensorimotor and associative subregions of the denervated striatum. Coadministration of (-)-OSU6162 with l-DOPA partially reversed the lesion- and l-DOPA-induced elevation of PPE expression and, by affecting PPE mRNA expression differentially on the intact and lesioned striatum, markedly reduced the side-to-side difference in PPE mRNA expression. The effects on PPE mRNA expression were apparent throughout the rostrocaudal extent of the putamen and the dorsal portions of the caudate nucleus. l-DOPA treatment resulted in an enhancement in PDyn mRNA expression in all functional compartments of the striatum. Coadministration of (-)-OSU6162 had no apparent influence on these l-DOPA-induced changes in PDyn mRNA expression. The present results suggest that (-)-OSU6162 acts primarily by modifying striatal output via the indirect pathway.

Interactions between monoamines, glutamate, and GABA in schizophrenia: new evidence.

In spite of its proven heuristic value, the dopamine hypothesis of schizophrenia is now yielding to a multifactorial view, in which the other monoamines as well as glutamate and GABA are included, with a focus on neurotransmitter interactions in complex neurocircuits. The primary lesion(s) in schizophrenia does not necessarily involve any of these neurotransmitters directly but could deal with a more general defect, such as a faulty connectivity of developmental origin. Nevertheless, a precise identification of neurotransmitter aberrations in schizophrenia will probably provide clues for a better understanding of the disease and for the development of new treatment and prevention strategies.

Effects of acute and repeated treatment with a novel dopamine D2 receptor ligand on L-DOPA-induced dyskinesias in MPTP monkeys.

(S)-(-)-3-(3-(methylsulfonyl)phenyl)-1-propylpiperidine ((-)-OSU6162) is a phenylpiperidine derivative which exhibits low affinity to the dopamine D2 receptor in vitro. However, in vivo, positron emission tomography scanning studies show that the compound displaces the selective dopamine D2 receptor antagonist, raclopride. We have evaluated, in this study, the effect of (-)-OSU6162, on L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesias in a primate model of Parkinson's disease. Five 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated cynomolgus monkeys with a stable parkinsonian syndrome and reproducible dyskinesias to L-DOPA were used in this study. The monkeys were housed in observation cages equipped with an electronic motility monitoring system. They were injected subcutaneously (s.c.) with L-DOPA methyl ester (125 mg per animal) plus benserazide (50 mg per animal; L-DOPA/benserazide) alone or in combination with (-)-OSU6162 (1.0, 3.0, 6.0 or 10 mg/kg, s.c.). Subcutaneous injection of sterile saline was used as control. L-DOPA/benserazide increased locomotion and improved parkinsonism but also induced dyskinesias. Co-administration of (-)-OSU6162 with L-DOPA/benserazide produced a significant reduction in L-DOPA-induced dyskinesias. This improvement in L-DOPA-induced dyskinesias occurred mainly at the onset of the L-DOPA/benserazide effect as reflected by an increase in the duration of the "ON" state without dyskinesias up to 3.4 fold after (-)-OSU6162 co-administration as compared to L-DOPA/benserazide alone. The anti-dyskinetic effect of (-)-OSU6162 was maintained during 14 days and no tolerance to this effect was observed. Our data suggests that (-)-OSU6162 could be of significant clinical value to reduce L-DOPA-induced dyskinesias in fluctuating advanced Parkinson's disease patients.

Motor effects of (-)-OSU6162 in primates with unilateral 6-hydroxydopamine lesions.

The effects of the novel compound, (-)-OSU6162 ((S)-(-)-3-methylsulfonylphenyl-1-propylpiperidine), on rotational behavior induced by dopamine receptor agonists was investigated in common marmosets (Callithrix jacchus) with unilateral 6-hydroxydopamine lesions. (-)-OSU6162 per se displayed no effect on the animals' behavior. On the other hand, pretreatment with (-)-OSU6162 attenuated rotational behavior induced by apomorphine (apomorphini hydrochloridum), L-DOPA (3,4-dihydroxyphenylalanine), and the dopamine D2 receptor agonist, quinpirole (trans-(-)-4aR-4,4a, 5,6,7,8,8a,9-octahydro-5-propyl-1H-pyrazolol[3,4-g]quinoline hydrochloride), without inducing motor impairment such as akinesia or dystonia. In addition, treatment with (-)-OSU6162 for 5 consecutive days almost completely abolished the rotational behavior provoked by apomorphine and produced a transient subsensitization of such apomorphine-induced effects after it was discontinued. Moreover, pretreatment with (-)-OSU6162 in two monkeys augmented the rotational behavior elicited by the dopamine D1 receptor agonists, SKF-81297 (R(+)-6-chloro-7,8,dihydroxy-1-phenyl-2,3,4, 5-tetrahydro-1H-3-benzazepine hydrobromide) and A-77636 ((-)-(1R, 3S)-3-adamantyl-1-(aminomethyl)-3,4-dihydro-5, 6-dihydroxy-1H-2-benzopyran hydrochloride). The findings indicate that (-)-OSU6162 can exert indirect state-dependent effects that differentially affect dopamine D1 and dopamine D2 receptor agonist-induced behavior.

A comparison of 11C-labeled L-DOPA and L-fluorodopa as positron emission tomography tracers for the presynaptic dopaminergic system.

11C-labeled 3,4-Dihydroxy-phenyl-L-alanine (L-DOPA) and L-fluorodopa were used as tracers for the functional state of the presynaptic dopamine system in anesthetized monkeys with positron emission tomography. The radiotracer disposition in brain tissue and plasma were studied and effects induced by pharmacologic challenges were evaluated. 6R-L-erythro-5,6,7,8-tetrahydrobiopterin (6R-BH4) increased the striatal influx rate constant, e.g., striatal K(i) for L-[beta-11C]DOPA, but it induced no effect on the K(i)-value using L-[beta-11C]-6-fluorodopa. Studies of radiolabeled tracer and metabolites in plasma showed substantial differences between the two tracers. At baseline conditions, 60% unchanged L-[beta-11C]DOPA was detected in plasma 50 minutes after tracer injection and the 3-O-methylated fraction accounted for 25% of total radioactivity. For L-[beta-11C]-6-fluorodopa, the relation was inverse; about 25% unchanged tracer and 60% 3-O-methyl metabolite were present in plasma after 50 minutes. A site-specific 11C-labeling in the carboxylic position in the molecules revealed a significant specific retention of radioactivity in striatum with L-[car-boxy-11C]-6-fluorodopa but not with L-[carboxy-11C]DOPA. The 3-O-methyl metabolite of L-DOPA is known to pass the blood-brain barrier and may interfere with the calculation of the K(i)value using a brain reference region. Thus, extensive 3-O-methylation in circulation of the fluorinated analog could obscure the detectability of potential functional change in striatal K(i) of the tracer when using a reference tissue model for calculation.

Regulation of dopaminergic activity in early Parkinson's disease.

Parkinson's disease (PD) is characterized by an uneven and progressive loss of nigrostriatal dopaminergic neurons. It is hypothesized that the physiological basis for the therapeutic response in early stages of PD is the ability for the partially and unevenly denervated dopaminergic system to restore and normalize dopaminergic influence in functionally segregated subregions of the basal ganglia. To investigate this hypothesis, patients with early and uncomplicated PD were investigated with positron emission tomography by using a two-tracer protocol yielding a measure of dopamine transporter-corrected dopamine synthesis capacity. Compared with controls, patients with PD exhibited a considerable increase in dopamine transporter-corrected dopamine synthesis capacity. The increase showed an inverse dependence on the structural integrity in as much as the highest rate was measured in the most denervated region, the dorsal part of putamen (198% of control value). A therapeutic challenge with antiparkinsonian medication state-dependently decreased dopaminergic activity. Thus, it is demonstrated that dopaminergic degeneration in PD is accompanied by a conspicuous acceleration of presynaptic dopaminergic activity, which is state-dependently down-regulated by dopaminomimetic treatment. It is suggested that homeostatic mechanisms acting to maintain congruity within the dopaminergic system are functionally intact in early PD.

Effects of the substituted (S)-3-phenylpiperidine (-)-OSU6162 on PET measurements of [11C]SCH23390 and [11C]raclopride binding in primate brains.

The substituted (S)-3-phenylpiperidine (-)-OSU6162 belongs to a novel class of functional modulators of dopaminergic systems. In vivo, (-)-OSU6162 has a unique stabilising profile on dopaminergic functions. In vitro this compound exhibits low affinity for the dopamine D2 receptor, but due to its similarity to neuroleptics on brain dopaminergic neurochemistry and different postsynaptic effects it has been characterised as a preferential dopamine autoreceptor antagonist. To further clarify the effects of (-)-OSU6162 on the postjunctional nigrostriatal dopaminergic system, dopamine receptor binding was measured in rhesus monkeys (Macaca mulatta) by positron emission tomography (PET) using the D1 and D2 dopamine receptor radioligands [11C]SCH23390 and [11C]raclopride respectively, before and during continuous intravenous infusions of(-)-OSU6162. Additionally, the test-retest variability of sequential [11C]SCH23390 scans was estimated. Following the administration of (-)-OSU6162, [11C]raclopride binding in striatum was dose-dependently decreased with a 76% reduction occurring after 3.0 mg/kg per h continuous infusion. Whereas (-)-OSU6162 in the lower doses had no effect on [11C]SCH23390 binding, the highest dose, 3.0 mg/kg per h, increased [11C]SCH23390 binding, which may indicate a potentiating effect on D1 dopamine receptor mediated functions. Thus, in contrast to the conditions in vitro, (-)-OSU6162 produces a high displacement of raclopride from D2 receptors in vivo.

NMDA-receptor activity visualized with (S)-[N-methyl-11C]ketamine and positron emission tomography in patients with medial temporal lobe epilepsy.

PURPOSE: To determine whether neurochemical activation of the N-methyl-D-aspartate (NMDA) receptor-gated ion channel shows quantitative changes, measured as binding of 11C-labeled (S)-[N-methyl]ketamine, in patients with medial temporal lobe epilepsy (MTLE). METHODS: Eight patients with MTLE who were evaluated regarding epilepsy surgery underwent positron emission tomography (PET) with (S)-[N-methyl-11C]ketamine. The presurgical investigations included magnetic resonance imaging (MRI), PET with 18F-fluoro-deoxyglucose (18FDG), and seizure monitoring by using video-EEG. The uptake of (S)-[N-methyl-11C]ketamine in the temporal lobe of ictal onset was compared with the contralateral side and correlated to changes in regional glucose metabolism measured by PET with 18FDG. RESULTS: (S)-[N-methyl-11C]ketamine rapidly reached the brain, and high radioactivities were measured in the striatum, thalamic nuclei, and cortical regions. Overall the brain uptake and regional binding potentials of (S)-[N-methyl-11C]ketamine were similar to measurements observed previously in healthy controls. However, 20 min after administration, when blood flow influence was negligible, a side-to-side comparison revealed a 9-34% reduction of tracer radioactivity in the temporal lobes of ictal onset. At earlier times, the differences in binding potentials were less pronounced, 9-21%. The magnitude and distribution of the reduction were similar to the metabolic pattern seen on PET scans with 18FDG. CONCLUSIONS: Radioactivity uptake of intravenously administered (S)-[N-methyl-11C]ketamine was reduced in temporal lobes of ictal in patients with TLE. This may reflect reduced NMDA-receptor density, reduced perfusion, focal atrophy, or other factors.

Dopamine autoreceptor function is lost in advanced Parkinson's disease.

OBJECTIVE: Regional presynaptic dopaminergic function and its regulation by dopamine agonists in different stages of PD can be measured by L-[11C]dopa and PET. In the current investigation, we studied the effects of therapeutic apomorphine on L-[11C]dopa uptake in patients with early and advanced PD. BACKGROUND: With disease progression and chronic dopamine agonist treatment, motor response complications supervene in a majority of PD patients. It is assumed that both presynaptic and postsynaptic changes in the dopaminergic system act to modify dopaminergic efficacy. METHODS: Patients with early and advanced stages of PD were included in the study. All patients were investigated twice with PET and L-[11C]dopa drug free and during a subsequent standardized therapeutic apomorphine infusion. RESULTS: Subregional analysis of the striatum showed differences in the effects of apomorphine infusion on the L-[11C]dopa influx rate in the two patient categories. In patients with early and uncomplicated PD, apomorphine infusion decreased the L-[11C]dopa influx rate. This decrease was most pronounced in the dorsal part of the putamen. In advanced PD patients, apomorphine did not affect the striatal L-[11C]dopa influx rate. CONCLUSIONS: We suggest that in mild and stable PD an upregulated presynaptic inhibitory feedback regulation, particularly in the dorsal putamen, acts to maintain congruity within the dopaminergic system in response to antiparkinsonian medication. However, this inhibitory feedback regulation is diminished with the progression of nigrostriatal degeneration and chronic dopamine agonist treatment.

Absorption of L-DOPA from the proximal small intestine studied in the rhesus monkey by positron emission tomography.

Positron emission tomography (PET) seems to be a valuable method for the understanding of intestinal absorption mechanisms, for simultaneous quantitation of absorption rate and distribution kinetics to the tissues of interest after oral drug delivery. PET was evaluated in three Rhesus monkeys for quantitation of the absorption rate from the gastrointestinal tract and the distribution kinetics into different organs. To obtain optimal standardized conditions for the measurement of absorption the drug was administered via a naso-duodenal catheter directly to the absorption site in the proximal small intestine. l-DOPA was used as study drug given in a suspension together with carbidopa and the radiomarker l-[beta-11C]DOPA. The l-DOPA suspension was given into the duodenum without and after administration of a suspension of six l-amino acids (120 mM) in order to investigate any interaction on the intestinal absorption and distribution of l-DOPA into the liver and brain tissue. Intestinal absorption was in general minor during the first study period and higher together with administered l-amino acids. The somewhat contradictory result with increased absorption when amino acids were present in the intestinal lumen, may be a consequence of increased intestinal motility initiated by the nutrient load.

Effect of apomorphine infusion on dopamine synthesis rate relates to dopaminergic tone.

The effects of apomorphine on the striatal L-[11C]DOPA influx rate was examined in anaesthetized Rhesus monkeys using positron emission tomography (PET). In comparison with baseline conditions, the addition of a continuous infusion of apomorphine produced decreases in the striatal L-[11C]DOPA influx rate in all the monkeys examined. The effect of apomorphine infusion also showed a dose-dependent trend. In individual monkeys, the magnitude of the effect showed a baseline dopaminergic tone-dependency; that is, the effect of apomorphine was most pronounced in monkeys with high baseline influx rates, and in monkeys with lower baseline values apomorphine induced a weaker effect. Studies of radiolabeled tracer and radiolabeled metabolites formed in plasma confirmed that apomorphine infusion did not induce any change in the peripheral elimination or metabolite formation of L-[11C]DOPA. The decreased striatal L-[11C]DOPA influx rate induced by apomorphine was interpreted as an agonist effect on dopamine autoreceptors regulating the dopamine synthesis rate. The observation of a baseline dopaminergic tone-dependent effect is in agreement with earlier results showing this influence on the striatal influx rate as measured with the tracer L-[11C]DOPA. A priori, it can be established that L-[11C]DOPA and PET provide a method not only to study the structural integrity of the presynaptic dopaminergic system but also to study the homeostasis-regulating mechanisms of this neurotransmitter system in vivo. The ability to measure condition-dependent effects in individuals should be of great importance in determining specific pathophysiological mechanisms underlying degenerative and functional disorders affecting the dopaminergic system.

[How can PET scan be used in Parkinson disease?]. / Hur kan PET användas kliniskt vid Parkinson's sjukdom?

PET (positron emission tomography) has yielded manifest improvements in our knowledge of Parkinson's disease, in terms of pathological and pharmacological aspects. Since PET was introduced in study of Parkinson's disease 15 years ago, the technique has been steady refined, and more tracers are becoming available. The possibility of monitoring the dopamine system in longitudinal studies will no doubt become cornerstone in the evaluation of neuroprotective therapies.

Effects of the substituted (S)-3-phenylpiperidine (-)-OSU6162 on PET measurements in subhuman primates: evidence for tone-dependent normalization of striatal dopaminergic activity.

(-)-OSU6162 is a substituted (S)-3-phenylpiperidine derivative which exhibits some affinity to the dopamine D2 receptor family. In vivo, the compound displays a unique normalizing profile on psychomotor activity by an intriguing mixture of stimulatory and inhibitory properties. In the present investigation, some of the effects of (-)-OSU6162 on central dopaminergic function were studied by positron emission tomography (PET) and L-[11C]DOPA in anaesthetized female rhesus monkeys. (-)-OSU6162 displayed a dopaminergic tone-dependent effect with a reduction in the striatal L-[11C]DOPA influx rate in monkeys with high baseline values and an increased striatal L-[11C]DOPA influx rate in animals with low baseline values. Infusion of (-)-OSU6162 for a whole day resulted in a stable effect with no evidence of tolerance. (-)-OSU6162 also stabilized dopaminergic function by attenuating the upregulation of the striatal L-[11C]DOPA influx rate which has previously been shown to occur following 6R-BH4 or 6R-BH4 + L-tyrosine infusions. This "Protean" effect of (-)-OSU6162 on the striatal dopaminergic function corresponds to previous behavioral observations in intact animals and demonstrates a true functional correlation to the measures obtained with L-[11C]DOPA and PET. The normalizing and stabilizing profile of (-)-OSU6162 should be of value in treating a variety of disorders where an underlying dysregulation or disruption of dopaminergic function can be assumed.

Reversible chorea in primary antiphospholipid syndrome.

A 20-year-old woman with acute chorea induced by primary antiphospholipid syndrome was studied by using fluorodeoxyglucose and positron emission tomography (PET). PET sessions were conducted during an episode of severe chorea and after recovery. The symptoms predominantly affected the right side of her face and body, and PET demonstrated a corresponding increase in lentiform and caudate nucleus metabolism prevailing on the left side. After recovery, PET showed normal values in the regions previously studied. This study adds further evidence to support the theory that acute choreas are somehow the result of striatal hypermetabolism.

Synthesis of [11C-methyl]-(-)-OSU6162, its regional brain distribution and some pharmacological effects of (-)-OSU6162 on the dopaminergic system studied in the rhesus monkey by positron emission tomography.

The labelling of the presynaptic dopamine receptor antagonist (-)-OSU6162, ((S)-(-)-3-(3-(methylsulfonyl)phenyl)-1-propylpiperidine) was performed by an alkylation with [11C]methyl iodide of the thio anion (-)-OSU1281, followed by a selective oxidation to the corresponding methyl sulfone, [11C-methyl]-(-)-OSU6162. The total radiochemical yield calculated from the produced [11C]carbon dioxide to final product was about 25% and the time of synthesis was in the range of 40 min from end of bombardment. The synthesis of the precursor, (-)-OSU1281, was performed from (-)-3PPP in a three-step synthesis. The regional brain distribution of (-)-OSU6162 radiolabelled with 11C was studied in rhesus monkeys by means of positron emission tomography, PET. [11C-Methyl]-(-)-OSU6162 was rapidly and uniformly distributed to gray matters of the brain, and no decrease of radioactivity uptake in the brain was seen after pretreatment with 1 to 3 mg/kg/h of (-)-OSU6162. The effect of doses of 1 to 3 mg/kg/h of (-)-OSU6162 on the dopamine binding was studied by PET using [11C-methyl]raclopride. Radioactivity in the striatum was significantly and dose-dependently decreased by (-)-OSU6162 (r = 0.88), supporting competition with dopamine for selective binding to dopamine receptors.