Imaging Nicotine- and Amphetamine-Induced Dopamine Release in Rhesus Monkeys with [11C]PHNO vs [11C]raclopride PET

The radiotracer [¹¹C]PHNO may have advantages over other dopamine (DA) D₂/D₃ receptor ligands because, as an agonist, it measures high-affinity, functionally active D₂/D₃ receptors, whereas the traditionally used radiotracer [¹¹C]raclopride measures both high- and low-affinity receptors. Our aim was to take advantage of the strength of [¹¹C]PHNO for measuring the small DA signal induced by nicotine, which has been difficult to measure in preclinical and clinical neuroimaging studies. Nicotine- and amphetamine-induced DA release in non-human primates was measured with [¹¹C]PHNO and [¹¹C]raclopride positron emission tomography (PET) imaging. Seven adult rhesus monkeys were imaged on a FOCUS 220 PET scanner after injection of a bolus of [¹¹C]PHNO or [¹¹C]raclopride in three conditions: baseline; preinjection of nicotine (0.1 mg/kg bolus+0.08 mg/kg infusion over 30 min); preinjection of amphetamine (0.4 mg/kg, 5 min before radiotracer injection). DA release was measured as change in binding potential (BP_ND). Nicotine significantly decreased BP_ND in the caudate (7±8%), the nucleus accumbens (10±7%), and in the globus pallidus (13±15%) measured with [¹¹C]PHNO, but did not significantly decrease BP_ND in the putamen or the substantia nigra or in any region when measured with [¹¹C]raclopride. Amphetamine significantly reduced BP_ND in all regions with both radiotracers. In the striatum, larger amphetamine-induced changes were detected with [¹¹C]PHNO compared with [¹¹C]raclopride (52–64% vs 33–35%, respectively). We confirmed that [¹¹C]PHNO is more sensitive than [¹¹C]raclopride to nicotine- and amphetamine-induced DA release. [¹¹C]PHNO PET may be more sensitive to measuring tobacco smoking-induced DA release in human tobacco smokers.     

Development of [123I]IPEB and [123I]IMPEB as SPECT Radioligands for Metabotropic Glutamate Receptor Subtype 5

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In vivo (123)I IBZM SPECT imaging of striatal dopamine 2 receptor occupancy in schizophrenic patients

RATIONALE: Single photon emission computed tomography (SPECT) using (123)I iodobenzamide (IBZM) as tracer substance has been shown to be a useful tool to visualize dopamine 2 (D2) receptor occupancy. OBJECTIVES: We investigated the striatal D2 receptor occupancy of zotepine which is referred to the class of atypical antipsychotic drugs. METHODS: (123)I IBZM and SPECT were used to visualize striatal dopamine 2 (D2) receptor occupancy in zotepine-treated schizophrenic patients. Two groups of schizophrenic patients receiving either 150 mg/day zotepine (n=6) or 300 mg/day (n=6) underwent examination. For the quantification of striatal D2 receptor occupancy, striatal IBZM binding in patients treated with antipsychotics was compared to untreated healthy controls (n=8) reported earlier. RESULTS: Zotepine led to a mean overall striatal D2 receptor occupancy of 73%. Patients with 150 mg daily showed a significantly lower occupancy (65.8%, SD=6.2) than patients with 300 mg/day (77.8%, SD=10.7; P<0.05). No clinically relevant extrapyramidal side effects occurred during treatment with zotepine. CONCLUSIONS: There was no correlation between the degree of striatal D2 receptor occupancy and clinical improvement.     

Validity of in vivo [123I]beta-CIT SPECT in detecting MDMA-induced neurotoxicity in rats.

This study investigated the ability of a high-resolution pinhole single-photon emission computed tomography (SPECT) system, with [(123)I]beta-CIT as a radiotracer, to detect 3,4-methelenedioxymethamphetamine (MDMA, 'Ecstasy')-induced loss of serotonin transporters (SERTs) in the living rat brain. In vivo striatal and thalamic [(123)I]beta-CIT binding ratios, representing specific binding to dopamine and serotonin transporters, respectively, were determined 7 days before as well as 10 days after treatment of rats with neurotoxic doses of MDMA using SPECT. At the end of the experiment, radioactivity ratios were also determined ex vivo, and compared to control data. Both in vivo and ex vivo, thalamic, but not striatal, uptake ratios were statistical significantly reduced after MDMA treatment. These data show that [(123)I]beta-CIT SPECT may be able to detect MDMA-induced loss of SERTs. Therefore, this may be a promising technique to perform serial studies on MDMA-induced serotonergic neurotoxicity in living small animals.     

[123I]β-CIT SPECT imaging of dopamine transporter availability after mazindol administration in human cocaine addicts

The in vivo potency of mazindol for binding to striatal dopamine transporters (DAT) was assessed by [¹²³I]β-CIT ([¹²³I]2β-carbomethoxy-3β-(4-iodophenyl)tropane) single photon emission computed tomography (SPECT). Cocaine-dependent subjects (n=12) underwent three SPECT scans; one before, between, and after subchronic (1 week) administration of 2mg/day and 4mg/day mazindol. For each scan, subjects were injected with [¹²³I]β-CIT and imaged 24h later under equilibrium conditions. Results showed a statistically significant main effect of mazindol dose (df=2, F=10.30, P<0.001, repeated measures ANOVA) in reducing the specific to non-displaceable equilibrium partition coefficient, V₃″ (a measure proportional to DAT binding potential). Regression analysis of the logit transformed data enabled estimation of the 50% displacement dose of mazindol (ED₅₀=30mg/ day). These data suggest that low doses of mazindol (i.e., 2–4mg) occupy a small percentage (i.e., <25%) of DAT in human cocaine abusers and that much higher, potentially intolerable doses (i.e., ≥30mg/day) may be required to antagonize significantly cocaine binding in vivo. Received: 14 November 1996/Final version: 17 December 1997     

SPECT imaging of the benzodiazepine receptor in non-human primate brain with [123I]Ro 16-0154.

We have used SPECT (single photon emission computed tomography) imaging in non-human primates to examine the time course and pharmacological specificity of 123I-labeled Ro 16-0154 as an in vivo probe of the benzodiazepine receptor. Maximal brain uptake was reached approximately 70 min post i.v. administration of the radioligand and represented approximately 10% of the injected dose. The regional distribution of radioactive densities was consistent with the known distribution of benzodiazepine receptors in primate brain, with highest uptake localized over the occipital area. Washout of radioactivity was relatively slow with a rate of 3% per hour after the time of peak radioactivity. Injection of the benzodiazepine antagonist Ro 15-1788 (0.2-0.3 mg/kg i.v.) caused a rapid decrease of more than 90% of radioactivity from brain. In summary, [123I]Ro 16-0154 is a promising in vivo SPECT radioligand for the benzodiazepine receptor, with high brain uptake, a stable period of peak radioactivity, appropriate regional distribution, and ability to be displaced by other benzodiazepine receptor agents.     

Higher serotonin transporter occupancy after multiple dose administration of escitalopram compared to citalopram: an [123I]ADAM SPECT study

Objectives Previous studies have investigated the occupancy of the serotonin reuptake transporter (SERT) after clinical doses of citalopram and other selective serotonin reuptake inhibitors. In the present study, the occupancies of SERT after multiple doses of escitalopram and citalopram were compared using the radioligand [¹²³I]ADAM and single photon emission computed tomography (SPECT). Methods Fifteen healthy subjects received escitalopram 10 mg/day (n = 6) or citalopram 20 mg/day (n = 9) for a total of 10 days. SERT occupancies in midbrain were determined with SPECT and [¹²³I]ADAM at three different time points: at baseline (no medication) and at 6 and 54 h after last drug intake. Results At 6 h after the last dose, mean SERT occupancies were 81.5 ± 5.4% (mean±SD) for escitalopram and 64.0 ± 12.7% for citalopram (p < 0.01). At 54 h after the last dose, mean SERT occupancies were 63.3 ± 12.1% for escitalopram and 49.0 ± 11.7% for citalopram (p < 0.05). The plasma concentrations of the S-enantiomer were of the same magnitude in both substances. For both drugs, the elimination rate of the S-enantiomer in plasma was markedly higher than the occupancy decline rate in the midbrain. Conclusion The significantly higher occupancy of SERT after multiple doses of escitalopram compared to citalopram indicates an increased inhibition of SERT by escitalopram. The results can also be explained by an attenuating effect of R-citalopram on the occupancy of S-citalopram at the SERT.     

Higher occupancy of muscarinic receptors by olanzapine than risperidone in patients with schizophrenia. A[123I]-IDEX SPECT study

RATIONALE: In vitro data have shown anticholinergic properties of the atypical antipsychotic drug olanzapine. Substantial occupancy of muscarinic receptors may be an explanation for the low incidence of extrapyramidal side effects induced by olanzapine. OBJECTIVES: To obtain an in vivo measurement of muscarinic receptor occupancy by olanzapine compared with risperidone in patients with schizophrenia stabilised on medication. METHODS: Five patients with schizophrenia treated with olanzapine and five patients treated with risperidone were studied. Muscarinic receptor occupancy in the striatum and cortex was studied in vivo with SPECT using [123I]-IDEX as a radioligand. SPECT data were compared with those of six healthy subjects. RESULTS: Patients stabilised on olanzapine showed significantly lower mean (+/-SD) striatal and cortical (1.50+/-0.21 and 1.51+/-0.22, respectively) muscarinic receptor binding ratios of [123I]-IDEX (reflecting higher levels of muscarinic receptor occupancy) than controls (3.91+/-0.61 and 3.65+/-0.70, respectively). Furthermore, [123I]-IDEX binding ratios in patients treated with risperidone were slightly lower than controls, reaching significance only in the striatum (2.99+/-0.27 versus 3.91+/-0.61, for risperidone and controls). CONCLUSIONS: The substantial occupancy of muscarinic receptors in the striatum and cortex by olanzapine may be an explanation for the low incidence and severity of extrapyramidal side effects of this antipsychotic drug. Furthermore, it may also explain the anticholinergic side effects of olanzapine.     

Release and Metabolism of Dopamine in a Clonal Line of Pheochromocytoma (PC12) Cells Exposed to Fenthion

The effects of an organophosphate (OP) pesticide, fenthion (FEN),on the release and metabolism of dopamine were evaluated ina clonal line of rat pheochromocytoma (PC 12) cells. HPLC wasused to determine media concentrations of DA and the DA metabolitesnorepinephrine (NE), 3,4-dihydroxyphenylacetic acid (DOPAC),and homovanillic acid (HVA). The FEN formulation solvent didnot significantly affect DA metabolism. In the first study,cultures were treated with l0^–5 or l0^–6 M FEN orl0^–5 M neostigmine, a non-OP acetylcholinesterase inhibitor.Concentrations of both catecholamines were elevated in culturestreated with l0^–5 M FEN by 2.8-fold for DA and 3.5-foldfor NE. Neostigmine effects were of smaller magnitude and DAwas decreased after 24 hr. Cultures were also treated with depolarizinglevels of K⁺ but the effect of FEN was not altered, suggestingthat FEN does not act by increasing DA release. In the secondstudy, the effect of l0^–6 M FEN was evaluated in culturestreated with the DA uptake inhibitor benztropine, the monoamineoxidase (MAO) inhibitor pargyline, or the catechol-O-methyltransferase(COMT) inhibitor tropolone. Inhibitor effects were consistentwith their known mechanisms of action. In all cultures treatedwith FEN, the ratio HVA/DOPAC was decreased after 3 and 6 hrof exposure. A decrease in HVA/DOPAC was also observed in culturestreated with neostigmine and tropolone. In combination withpargyline, FEN decreased DA in contrast to its usual effectof increasing DA. Neither the stimulation of DA release northe inhibition of DA uptake affected the observed action ofFEN in PC 12 cultures. Results were supportive ofthe abilityof FEN to inhibit the catabolism of DOPAC to HVA, with a subsequentincrease in DA levels.     

Subchronic Toxicity, Metabolism, and Pharmacokinetics of the Aminobenzamide Anticonvulsant Ameltolide (LY2O1 116) in Rhesus Monkeys

Studies were undertaken to define the subchronic toxicologicprofile of ameltolide, an aminobenzamide anticonvulsant, inyoung adult rhesus monkeys. Daily doses of ameltolide, dissolvedin 10% aqueous acacia, were administered orally via nasogastricintubation at dosages of 5, 10, 20, 45, and 100 mg/kg. Deathsoccurred in two monkeys, one each at 45 and 100 mg/kg, whichwere directly attributable to the effects of the compound. Theexact cause of death in these monkeys was not readily apparent.A third monkey (100 mg/kg) was killed moribund on Day 82 ofthe study due to conditions not directly related to treatment.Clinical signs in monkeys treated with 100 mg/kg included convulsions, diarrhea, weakness, inappetance, vomition, and ataxia.Plasma concentrations of the N-acetyl metabolite of ameltolidewere greater than parent drug concentrations by one to two ordersof magnitude. Mean area under the plasma-time curve (AUC) valuesfor ameltolide were larger than expected at doses of 20 mg/kgor greater, while AUC values for the metabolite were less thanexpected at 45 and 100 mg/kg. These findings suggest a saturationof metabolism and/or excretion at the two higher doses. Similarnonlinearity was seen with mean peak concentrations for bothparent and metabolite. No specific target organ toxicity wasfound on histological evaluation of tissue sections. Methemoglobinconcentration was increased in monkeys given 45 or 100 mg ameltolide/kg.This change was not considered to be toxicologically importantas there were no corroborative clinical, gross, or histopathologicalfindings. A meltolide administered by nasogastric intubationat doses up to 20 mg/kg/day for 3 months did not cause any toxicologicallyimportant alterations in rhesus monkeys.     

Synthesis and biological evaluation of [125I]- and [123I]-4-iododexetimide, a potent muscarinic cholinergic receptor antagonist

A series of halogenated racemic analogues of dexetimide (1) was synthesized and their affinity for the muscarinic cholinergic receptor measured. One analogue, 4-iododexetimide (21), was efficiently labeled with 125I and 123I at high specific activity. In vitro binding studies and in vivo biodistribution studies suggest that 123I-labeled 21 may be useful for imaging muscarinic cholinergic receptors in the living human brain with single photon emission computed tomography.     

In vivo imaging of serotonin transporter occupancy by means of SPECT and [123I]ADAM in healthy subjects administered different doses of escitalopram or citalopram

Background Escitalopram is a dual serotonin reuptake inhibitor (SSRI) approved for the treatment of depression and anxiety disorders. It is the S-enantiomer of citalopram, and is responsible for the serotonin reuptake activity, and thus for its pharmacological effects. Previous studies pointed out that clinically efficacious doses of other SSRIs produce an occupancy of the serotonin reuptake transporter (SERT) of about 80% or more. The novel radioligand [¹²³I]ADAM and single photon emission computer tomography (SPECT) were used to measure midbrain SERT occupancies for different doses of escitalopram and citalopram.Methods Twenty-five healthy subjects received a single dose of escitalopram [5 mg (n=5), 10 mg (n=5), and 20 mg (n=5)] or citalopram [(10 mg (n=5) and 20 mg (n=5)]. Midbrain SERT binding was measured with [¹²³I]ADAM and SPECT on two study days, once without study drug and once 6 h after single dose administration of the study drug. The ratio of midbrain-cerebellum/cerebellum was the outcome measure (V3”) for specific binding to SERT in midbrain. Subsequently, SERT occupancy levels were calculated using the untreated baseline level for each subject. An E _max model was used to describe the relationship between S-citalopram concentrations and SERT occupancy values. Additionally, four subjects received placebo to determine test–retest variability.Results Single doses of 5, 10, or 20 mg escitalopram led to a mean SERT occupancy of 60±6, 64±6, and 75±5%, respectively. SERT occupancies for subjects treated with single doses of 10 and 20 mg citalopram were 65±10 and 70±6%, respectively. A statistically significant difference was found between SERT occupancies after application of 10 and 20 mg escitalopram, but not for 10 and 20 mg citalopram. There was no statistically significant difference between the SERT occupancies of either 10 mg citalopram or 10 mg escitalopram, or between 20 mg citalopram and 20 mg escitalopram. E _max was slightly higher after administration of citalopram (84%) than escitalopram (79%). In the test–retest study, a mean SERT “occupancy” of 4% was found after administration of placebo, the intraclass correlation coefficient was 0.92, and the repeatability coefficient was 0.25.Conclusion SPECT and [¹²³I]ADAM were used to investigate SERT occupancies after single doses of escitalopram or citalopram. The test–retest study revealed good reproducibility of SERT quantification. Similar SERT occupancies were found after administration of equal doses (in respect to mg) of escitalopram and citalopram, giving indirect evidence for a fractional blockade of SERT by the inactive R-citalopram.     

Pharmacokinetic Analysis of Benzodiazepine Receptor Binding of [123I]Iomazenil in Human Brain

Purpose. The purpose of this study is to evaluate the central benzodiazepine (BZP) receptor binding of iomazenil (IMZ) by pharmacokinetic analysis and to establish a methodology for the diagnosis of CNS disorders with abnormalities in BZP receptor binding. Methods. BZP receptor binding of IMZ was analyzed kinetically using plasma concentration-time profiles and dynamic single photon emission computed tomography (SPECT) data obtained after the intravenous administration of IMZ to patients with neuropsychiatric diseases. The analysis was based on a 3-compartmental model including the processes of both blood-brain barrier (BBB) transport and BZP receptor binding. Results. Hydrolized metabolite of IMZ was detected in plasma, indicating the need for separation by HPLC. The BBB influx clearance and the receptor binding potential of IMZ in the medial temporal region was reduced in the epileptic patient. Conclusions. Our findings suggest the possibility of detecting the epileptic focus by using our method.     

Long-Term Exposure to Oral Methylphenidate or dl-Amphetamine Mixture in Peri-Adolescent Rhesus Monkeys: Effects on Physiology,Behavior, and Dopamine System Development

The stimulants methylphenidate and amphetamine are used to treat children with attention deficit/hyperactivity disorder over important developmental periods, prompting concerns regarding possible long-term health impact. This study assessed the effects of such a regimen in male, peri-adolescent rhesus monkeys on a variety of cognitive/behavioral, physiological, and in vivo neurochemical imaging parameters. Twice daily (0900 and 1200 hours), for a total of 18 months, juvenile male monkeys (8 per group) consumed either an unadulterated orange-flavored solution, a methylphenidate solution, or a dl-amphetamine mixture. Doses were titrated to reach blood/plasma levels comparable to therapeutic levels in children. [¹¹C]MPH and [¹¹C]raclopride dynamic PET scans were performed to image dopamine transporter and D₂-like receptors, respectively. Binding potential (BP_ND), an index of tracer-specific binding, and amphetamine-induced changes in BP_ND of [¹¹C]raclopride were estimated by kinetic modeling. There were no consistent differences among groups on the vast majority of measures, including cognitive (psychomotor speed, timing, inhibitory control, cognitive flexibility), general activity, physiological (body weight, head circumference, crown-to-rump length), and neurochemical (ie, developmental changes in dopamine transporter, dopamine D₂ receptor density, and amphetamine-stimulated dopamine release were as expected). Cytogenetic studies indicated that neither drug was a clastogen in rhesus monkeys. Thus, methylphenidate and amphetamine at therapeutic blood/plasma levels during peri-adolescence in non-human primates have little effect on physiological or behavioral/cognitive development.     

New preparation of [123I]PE2I: investigation of the oxidation and purification steps

In order to simplify preparation of [¹²³I]PE2I, iodogen and hydrogen peroxide were examined as oxidants for the preparation of radioiodinated PE2I, e.g. (E)‐N‐(3‐iodoprop‐2‐enyl)‐2β‐carbomethoxy‐3β‐(4′‐tolyl) nortropane). Among the oxidizing compounds assayed, iodogen appears to afford the best results for this purpose (high radiochemical yield, high chemical purity and a reasonable reaction time). A simplified and efficient method is described here for the preparation of [¹²³I]PE2I based on the exchange of a ¹²³I tributyl tin analogue in oxidative conditions followed by purification by solid phase extraction (SPE). Using this method, [¹²³I]PE2I was obtained with a radio‐pharmaceutical yield over 60%, with chemical and radiochemical purities higher than 95% without the addition of a carrier (Na¹²⁷I) (2G Bq/nmol) or with a specific activity adjusted to 85–90 MBq/nmol in the presence of the carrier. Copyright © 2002 John Wiley & Sons, Ltd.     

Striatal dopamine-2 receptor occupancy as measured with [123I]iodobenzamide and SPECT predicted the occurrence of EPS in patients treated with atypical antipsychotics and haloperidol

RATIONALE: Extrapyramidal symptoms (EPS) are common with conventional antipsychotics. Clozapine and other novel antipsychotic substances with lower in vitro affinity for dopamine-2 (D(2)) receptors have a lower propensity to induce EPS. OBJECTIVE: We investigated whether striatal D(2) receptor occupancy predicted the occurrence of EPS with atypical antipsychotics and the typical neuroleptic haloperidol. METHODS: [(123)I]Iodobenzamide (IBZM) and single photon emission tomography (SPECT) were used to quantify receptor occupancy in 71 patients treated with antipsychotics. EPS were rated according to the Simpson-Angus scale (SAS). EPS were deemed clinically relevant, if the SAS score was > or = 5 and/or anticholinergic medication was required. Patients received atypical antipsychotic monotherapy for at least 14 days with amisulpride ( n=2), clozapine ( n=6), haloperidol ( n=10), olanzapine ( n=6), quetiapine ( n=4), risperidone ( n=14), sertindole ( n=13), or zotepine ( n=16). RESULTS: The striatal D(2) receptor occupancy ranged from < 20% to almost saturation. The lowest occupancy was seen with quetiapine and clozapine, the highest with haloperidol. Twenty-two of 71 patients (29%) experienced clinically relevant EPS. These patients displayed significantly higher mean striatal D(2) receptor occupancy (77%) than those without EPS (61%; P=0.002). We found a positive correlation between the percentage of striatal D(2) receptor occupancy and the SAS score ( r=0.28; P=0.02), despite 18 of these patients receiving anticholinergics, thus lowering their SAS score. CONCLUSIONS: Striatal D(2) receptor occupancy as measured with [(123)I]IBZM and SPECT predicted the occurrence of EPS in patients treated with atypical antipsychotics and haloperidol. In vivo imaging of brain receptors with SPECT may provide a useful clinical tool to titrate doses individually and avoid motor side effects in patients treated with novel antipsychotics.     

Binding kinetics of 123I[ADAM] in healthy controls: a selective SERT radioligand

[123I]ADAM (2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine) is a promising radioligand for in-vivo quantification of serotonin transporters (SERT) using single photon emission computed tomography (SPECT) in man. We performed tracer kinetic analysis in various brain regions to determine the optimum equilibrium time for SERT quantification with [123I]ADAM and SPECT. Radiosyntheses of [123I]ADAM were performed at MAP Medical Technologies Oy, Tikkakoski, Finland. Thirty healthy male volunteers (21-41 yr) received between 104 and 163 MBq [123I]ADAM intravenously as a bolus. Consecutively, multiple SPECT scans were performed between 14 and 420 min post-injection (p.i.) using a Siemens Multispect 3 camera. Reconstruction was performed applying filtered back projection with a Butterworth filter (cut-off 0.7, order 7) in 128x128 matrices. Regions of interest (ROI) were drawn manually on the individual T1-weighted magnetic resonance image (MRI) comprising midbrain/hypothalamus for specific binding to SERT, and the cerebellum as reference region. After re-orientation to the MRI, the ROI template was applied to SPECT studies. We generated time-activity curves for the ROI and calculated the ratio countstarget/countscerebellum minus 1 (=V3') as a measure for specific SERT binding. Counts were corrected for applied activity, acquisition time and body-weight. Peak uptakes were observed between 14 and 50 min after bolus injection. Counts per voxel were highest in the midbrain/hypothalamus, 798 (max. 872, min. 728), whereas 462 counts per voxel (max. 599, min. 412) were measured in the cerebellum at a mean time of 31 min p.i. Stable values for V3' reached 205-320 min p.i. Mean peak V3' value was 1.43 (95% CI 171-230) for the midbrain/hypothalamus at 205 min p.i. [123I]ADAM is a useful ligand for in-vivo quantification of human SERT by means of SPECT, with a comparatively better signal-to-noise ratio compared to beta-CIT. Our data suggest that the acquisition time for the SPECT scan is optimally, under pseudo-equilibrium conditions, between 205-320 min post-bolus injection of the tracer.