Biomedical subjects

Balázs Gulyás

Publications and source records attributed to Balázs Gulyás.

At least 19 recordsLinked to original sources

PubMed2006

Synthesis of 11C-labelled (R)-OHDMI and CFMME and their evaluation as candidate radioligands for imaging central norepinephrine transporters with PET.

(R)-1-(10,11-Dihydro-dibenzo[b,f]azepin-5-yl)-3-methylamino-propan-2-ol ((R)-OHDMI) and (S,S)-1-cyclopentyl-2-(5-fluoro-2-methoxy-phenyl)-1-morpholin-2-yl-ethanol (CFMME) were synthesized and found to be potent inhibitors of norepinephrine reuptake. Each was labelled efficiently in its methyl group with carbon-11 (t(1/2)=20.4 min) as a prospective radioligand for imaging brain norepinephrine transporters (NET) with positron emission tomography (PET). The uptake and distribution of radioactivity in brain following intravenous injection of each radioligand into cynomolgus monkey was examined in vivo with PET. After injection of (R)-[(11)C]OHDMI, the maximal whole brain uptake of radioactivity was very low (1.1% of injected dose; I.D.). For occipital cortex, thalamus, lower brainstem, mesencephalon and cerebellum, radioactivity ratios to striatum at 93 min after radioligand injection were 1.35, 1.35, 1.2, 1.2 and 1.0, respectively. After injection of [(11)C]CFMME, radioactivity readily entered brain (3.5% I.D.). Ratios of radioactivity to cerebellum at 93 min for thalamus, occipital cortex, region of locus coeruleus, mesencephalon and striatum were 1.35, 1.3, 1.3, 1.2 and 1.2, respectively. Radioactive metabolites in plasma were measured by radio-HPLC. (R)-[(11)C]OHDMI represented 75% of plasma radioactivity at 4 min after injection and 6% at 30 min. After injection of [(11)C]CFMME, 84% of the radioactivity in plasma represented parent at 4 min and 20% at 30 min. Since the two new hydroxylated radioligands provide only modest regional differentiation in brain uptake and form potentially troublesome lipophilic radioactive metabolites, they are concluded to be inferior to existing radioligands, such as (S,S)-[(11)C]MeNER, (S,S)-[(18)F]FMeNER-D(2) and (S,S)-[(18)F]FRB-D(4), for the study of brain NETs with PET in vivo.

Animals↗

PubMed2006

Atomoxetine occupies the norepinephrine transporter in a dose-dependent fashion: a PET study in nonhuman primate brain using (S,S)-[18F]FMeNER-D2.

RATIONALE: Atomoxetine is a potent and selective norepinephrine transporter (NET) reuptake inhibitor acting as a nonstimulant for the treatment of attention-deficit/hyperactivity disorder (ADHD). Previous positron emission tomography (PET) studies had failed to demonstrate the feasibility of measuring a dose-dependent and saturable NET occupancy in human brain using [11C]MeNER. OBJECTIVES: To determine if atomoxetine occupies NET in a dose-dependent fashion using (S,S)-[18F]FMeNER-D2 in nonhuman primate brain. METHODS: A total of eight PET measurements were performed in two cynomolgus monkeys. Each monkey was examined four times with PET: under baseline conditions and after steady-state infusion with 0.03, 0.06, or 0.12 mg/kg/h of atomoxetine. A prolonged intravenous (i.v.) infusion design was developed rather than an i.v. bolus to better mimic an oral absorption profile and to reach plasma steady state. RESULTS: During baseline conditions, (S,S)-[18F]FMeNER-D2 uptake was highest in the locus coeruleus, thalamus, mesencephalon, and the cingulate gyrus, whereas the radioactivity in the caudate was low. Peak equilibrium measurements were achieved using (S,S)-[18F]FMeNER-D2 in contrast to the previously reported data for [11C]MeNER. After administration of atomoxetine, a dose-dependent occupancy from 38 to 82% was observed for various brain regions known to contain high densities of NET. CONCLUSIONS: This is the first in vivo PET study to successfully demonstrate the ability to measure a dose-dependent change in NET occupancy in brain using (S,S)-[18F]FMeNER-D2. Furthermore, an asymptotic relationship between N-desmethylatomoxetine plasma concentration and NET occupancy was established. In total, these data encourage further PET studies using (S,S)-[18F]FMeNER-D2 in humans.

Adrenergic Uptake Inhibitors↗

PubMed2006

A comparison of recent parametric neuroreceptor mapping approaches based on measurements with the high affinity PET radioligands [11C]FLB 457 and [11C]WAY 100635.

In positron emission tomography (PET) studies, the detailed mapping of neuroreceptor binding is a trade-off between parametric accuracy and spatial precision. Logan's graphical approach is a straightforward way to quickly obtain binding potential values at the voxel level but it has been shown to have a noise-dependent negative bias. More recently suggested approaches claim to improve parametric accuracy with retained spatial resolution. In the present study, we used PET measurements on regional D2 dopamine and 5-HT1A serotonin receptor binding in man to compare binding potential (BP) estimates of six different parametric imaging approaches to the traditional Logan ROI-based approach which was used as a "gold standard". The parametric imaging approaches included Logan's reference tissue graphical analysis (PILogan), its version recently modified by Varga and Szabo (PIVarga), two versions of the wavelet-based approach, Gunn's basis function method (BFM) and Gunn et al.'s recent compartmental theory-based approach employing basis pursuit strategy for kinetic modeling (called DEPICT). Applicability for practical purposes in basic and clinical research was also considered. The results indicate that the PILogan and PIVarga approaches fail to recover the correct values, the wavelet-based approaches overcome the noise susceptibility of the Logan fit with generally good recovery of BP values, and BFM and DEPICT seem to produce values with a bias dependent on receptor density. Further investigations on this bias and other phenomena revealed fundamental issues regarding the use of BFM and DEPICT on noisy voxel-wise data. In conclusion, the wavelet-based approaches seem to provide the most valid and reliable estimates across regions with a wide range of receptor densities. Furthermore, the results support the use of receptor parametric imaging in applied studies in basic or clinical research.

Algorithms↗

PubMed2006

Optimization of semi-quantification in metabolic PET studies with 18F-fluorodeoxyglucose and 11C-methionine in the determination of malignancy of gliomas.

The treatment of the glioma patient depends on the nature of the lesion and on the aggressiveness of the tumor. The management of gliomas continues to be a challenging task, because morphological neuroimaging techniques do not always differentiate them from nontumoral lesions or high grade tumors from low grade lesions. Positron Emission Tomography (PET) offers the possibility of the in vivo quantitative characterization of brain tumors. Despite decades of useful application of PET in the clinical monitoring of gliomas, no consensus has been reached on the most effective image analysis approach for providing the best diagnostic performance under heavy-duty clinical diagnostic circumstances. The main objective of the present study was to find and validate optimal semi-quantitative search strategies for metabolic PET studies on gliomas, with special regard to the optimization of those metabolic tracer uptake ratios most sensitive in predicting histologic grade and prognosis. 11C-Methionine (11C-Met, n = 50) and/or 18F-Fluorodeoxyglucose (18F-FDG, n = 33) PET measurements were performed in 59 patients with primary and recurrent brain gliomas (22 high grade and 37 low grade tumors) in order to correlate the biological behavior and 11C-Met/18F-FDG uptake of tumors. Data were analyzed by region-of-interests (ROI) methods using standard uptake value calculation. Different ROI defining strategies were then compared with each other for two of the most commonly used metabolic radiotracers, 18F-FDG and 11C-Met, in order to determine their usefulness in grading gliomas. The results were compared to histological data in all patients. Both ANOVA and receiver operating characteristic (ROC) analysis indicated that the performance of 18F-FDG was superior to that of 11C-Met for most of the ratios. 18F-FDG is therefore suggested as the tracer of choice for noninvasive semi-quantitative indicator of histologic grade of gliomas. 11C-Methionine has been suggested as a complimentary tracer, useful in delineating the extent of the tumor. The best diagnostic performance was obtained by calculating the ratio of the peak 18F-FDG uptake of the tumor to that of white matter (p < 0.001; ANOVA). This metabolic tracer uptake ratio is therefore suggested as an easily obtained semi-quantitative PET indicator of malignancy and histological grade in gliomas.

Adolescent↗

PubMed2006

Effect of amphetamine on dopamine D2 receptor binding in nonhuman primate brain: a comparison of the agonist radioligand [11C]MNPA and antagonist [11C]raclopride.

PET measurements of stimulant-induced dopamine (DA) release are typically performed with antagonist radioligands that bind to both the high- and low-affinity state of the receptor. In contrast, an agonist radioligand binds preferentially to the high-affinity state and is expected to have greater sensitivity to DA, which is the endogenous agonist. [(11)C]MNPA, (R)-2-CH(3)O-N-n-propylnorapomorphine (MNPA), is a D(2) agonist radioligand with subnanomolar affinity to the D(2) receptor. The aim of the present study is to assess and compare the sensitivity of the agonist radioligand [(11)C]MNPA and antagonist radioligand [(11)C]raclopride to synaptic DA levels. Four cynomolgus monkeys were examined with [(11)C]MNPA and [(11)C]raclopride (16 PET measurements with each tracer) at baseline and after pretreatment with various doses of amphetamine. The effect of amphetamine was calculated by the change in binding potential (BP) analyzed with the multilinear reference tissue model (MRTM2). Amphetamine caused a reduction in [(11)C]MNPA BP of 4% at 0.1, 23% at 0.2, 25% at 0.5, and 46% at 1.0 mg/kg. [(11)C]Raclopride BP was reduced to a lesser extent by 2% at 0.1, 16% at 0.2, 15% at 0.5, and 23% at 1.0 mg/kg. The data were used to estimate the in vivo percentage of high-affinity state receptors to be approximately 60%. These results demonstrate that [(11)C]MNPA is more sensitive than [(11)C]raclopride to displacement by endogenous DA, and that it may provide additional information about the functional state of the D(2) receptor in illnesses such as schizophrenia and Parkinson's disease.

Amphetamine↗

PubMed2006

The Budapest Meeting 2005 intensified networking on ethics of science: the case of reproductive cloning, germline gene therapy and human dignity.

This paper reports on the meeting of the Sounding Board of the EU Reprogenetics Project that was held in Budapest, Hungary, 6-9 November 2005. The Reprogenetics Project runs from 2004 until 2007 and has a brief to study the ethical aspects of human reproductive cloning and germline gene therapy. Discussions during The Budapest Meeting are reported in depth in this paper as well as the initiatives to involve the participating groups and others in ongoing collaborations with the goal of forming an integrated network of European resources in the fields of ethics of science.

Cloning, Organism↗

PubMed2005

[(11)C]MADAM, a new serotonin transporter radioligand characterized in the monkey brain by PET.

The aim of this study was to explore the potential of a new selective serotonin transporter (5-HTT) inhibitor, N,N-dimethyl-2-(2-amino-4-methylphenylthio)benzylamine (MADAM, K(i)=1.65 nM), as a PET radioligand for examination of 5-HTT in the nonhuman primate brain. MADAM was radiolabeled by an N-methylation reaction using [(11)C]methyl triflate and the binding was characterized by PET in four cynomolgus monkeys. Metabolite levels in plasma were measured by gradient high-performance liquid chromatography (HPLC). The radiochemical incorporation yield of [(11)C]MADAM was 75-80% and the specific radioactivity at the time of administration was 34-652 GBq/micromol (n=8). The highest uptake of radioactivity was observed in striatum, thalamus, mesencephalon, and the lower brainstem. Lower binding was detected in neocortex and the lowest radioactive uptake was found in the cerebellum. This distribution is in accordance with the known expression of 5-HTT in vitro. The fraction of the total radioactivity in monkey plasma representing unchanged [(11)C]MADAM was 20% at 45 min after injection, as measured by gradient HPLC. Pretreatment measurements, using unlabeled citalopram, GBR 12909, and maprotiline, as well as a displacement measurement, using unlabeled MADAM, confirmed that [(11)C]MADAM binds selectively and reversibly to 5-HTT, and support the use of the cerebellum as reference region. The present characterization of binding in the monkey brain suggests that [(11)C]MADAM is a potential PET radioligand for quantitative studies of 5-HTT binding in the human brain.

Animals↗

PubMed2005

Lack of effect of reserpine-induced dopamine depletion on the binding of the dopamine-D3 selective radioligand, [11C]RGH-1756.

The effect of reserpine induced dopamine depletion on the binding of the putative dopamine-D3 receptor ligand, [(11)C]RGH-1756 was examined in the monkey brain with positron emission tomography (PET). In a previous series of experiments, we have made an attempt to selectively label D3 receptors in the monkey brain using [(11)C]RGH-1756. Despite high selectivity and affinity of RGH-1756 in vitro, [(11)C]RGH-1756 displayed only low specific binding to D3 receptors in vivo. The aim of the present study was to examine whether low specific binding of [(11)C]RGH-1756 is caused by insufficient in vivo affinity of the ligand, or by high physiological occupancy of D3 receptors by endogenous dopamine (DA). PET experiments were performed in three monkeys under baseline conditions and after administration of reserpine (0.5 mg/kg). The results of the baseline measurements corresponded well to our earlier observations with [(11)C]RGH-1756. Reserpine caused no evident change in the regional distribution of [(11)C]RGH-1756 in the monkey brain, and no conspicuous regional accumulation of activity could be observed. After reserpine treatment there was no evident increase of specific binding and binding potential (BP) of [(11)C]RGH-1756. The lack of increased [(11)C]RGH-1756 binding after reserpine treatment indicates that competition with endogenous DA is not the predominant reason for the failure of the radioligand to label D3 receptors. Therefore, the low binding of [(11)C]RGH-1756 could largely be explained by the need for very high affinity of radioligand for D3 receptors in vivo, to obtain a suitable signal for the minute densities of D3 receptors expressed in the primate brain.

Adrenergic Uptake Inhibitors↗

PubMed2005

Effects of vinpocetine on the redistribution of cerebral blood flow and glucose metabolism in chronic ischemic stroke patients: a PET study.

The pharmacological effects of the neuroprotective drug vinpocetine, administered intravenously in a 14-day long treatment regime, on the cerebral blood flow and cerebral glucose metabolism in chronic ischemic stroke patients (n=13) were studied with positron emission tomography in a double-blind design. The regional and global cerebral metabolic rates of glucose (CMRglc) and cerebral blood flow (CBF) as well as vital physiological parameters, clinical performance scales, and transcranial Doppler parameters were measured before and after the treatment period in patient groups treated with daily intravenous infusion with or without vinpocetine. While the global CMRglc values did not change markedly as a result of the infusion treatment with (n=6) or without (n=7) vinpocetine, the global CBF increased and regional CMRglc and CBF values showed marked changes in several brain structures in both cases, with more accentuated changes when the infusion contained vinpocetine. In the latter case the highest rCBF changes were observed in those structures in which the highest regional uptake of labelled vinpocetine was measured in other PET studies (thalamus and caudate nucleus: increases amounting to 36% and 37%, respectively). The findings indicate that a 2-week long intravenous vinpocetine treatment can contribute effectively to the redistribution of rCBF in chronic ischemic stroke patients. The effects are most pronounced in those brain regions with the highest uptake of the drug.

Brain Chemistry↗

PubMed2005

Eburnamine derivatives and the brain.

The Apocynaceae plant family contains a great number of so called eburnamine-vincamine alkaloids. Quite a few of these alkaloids exert varied pharmacological activities on the cell multiplication, cardiovascular system, and brain functions. Many derivatives were also synthesized to find pharmacologically active compounds better characterized and safer to be administered than the natural plant alkaloids themselves. We concentrate on the eburnamine structures with cerebral activities in this review. Vincamine, vinburnine, vindeburnol, apovincaminate, and vinpocetine (cis-ethyl-apovincaminate) all share modulatory effects on brain circulation and neuronal homeostasis, bear antihypoxic and neuroprotective potencies to various degrees. The most eminent compound of this class of alkaloids is vinpocetine. Since its introduction to the market as a neuroprotective agent many non clinical and clinical studies proved vinpocetine's effects on calmodulin dependent phosphodiesterase E1, on sodium, calcium channels, peripheral benzodiazepine receptor, and glutamate receptors as well as its clinical usefulness in the treatment of post-ischaemic stroke disease states and various disorders of cerebrovascular origin. Lately, positron emission tomography studies proved that vinpocetine has a rapid uptake in the primate and human brain with a heterogeneous distribution pattern (preference areas: thalamus, basal ganglia, and visual cortex) both after intravenous and oral administration. Vinpocetine exerts beneficial effects in cerebral glucose metabolism and regional cerebral blood flow in chronic post-stroke patients.

Animals↗

PubMed2005

Preparation of highly specific radioactivity [18F]flumazenil and its evaluation in cynomolgus monkey by positron emission tomography.

A straightforward method for the preparation of no-carrier-added (n.c.a.) [18F]flumazenil via standard nucleophilic radiofluorination of the corresponding nitro-analog Ro 15-2344 has been developed. The labeling was performed by employing the K18F/kryptofix complex in DMF at 160 degrees C for 30 min and equimolar ratio [K/K2.2.2]+18F-/precursor. Under these conditions, an 18F incorporation rate into flumazenil was in the range of 55-60%. The final product was isolated by HPLC purification within a total synthesis time of 75 min and a radiochemical yield of about 30% (EOB). Human post-mortem whole-hemisphere autoradiography of brain sections demonstrated selective uptake of the radioligand in the areas of high density of the central benzodiazepine receptors (BZR). PET studies in a cynomolgus monkey and metabolite studies by HPLC demonstrated similar results by [18F]flumazenil as for [11C]flumazenil. In blocking experiments, almost all radioactivity was inhibited by the addition of unlabeled flumazenil. [18F]Flumazenil is a suitable radioligand for PET assessment of the BZR.

Animals↗

PubMed2005

A preliminary PET evaluation of the new dopamine D2 receptor agonist [11C]MNPA in cynomolgus monkey.

This study describes the preliminary positron emission tomography (PET) evaluation of a dopamine D(2)-like receptor agonist, (R)-2-(11)CH(3)O-N-n-propylnorapomorphine ([(11)C]MNPA), as a potential new radioligand for in vivo imaging of the high-affinity state of the dopamine D(2) receptor (D(2)R). MNPA is a selective D(2)-like receptor agonist with a high affinity (K(i)=0.17 nM). [(11)C]MNPA was successfully synthesized by direct O-methylation of (R)-2-hydroxy-NPA using [(11)C]methyl iodide and was evaluated in cynomolgus monkeys. This study included baseline PET experiments and a pretreatment study using unlabeled raclopride (1 mg/kg). High uptake of radioactivity was seen in regions known to contain high D(2)R, with a maximum striatum-to-cerebellum ratio of 2.23+/-0.21 at 78 min and a maximum thalamus-to-cerebellum ratio of 1.37+/-0.06 at 72 min. The pretreatment study demonstrated high specific binding to D(2)R by reducing the striatum-to-cerebellum ratio to 1.26 at 78 min. This preliminary study indicates that the dopamine agonist [(11)C]MNPA has potential as an agonist radioligand for the D(2)-like receptor and has potential for examination of the high-affinity state of the D(2)R in human subjects and patients with neuropsychiatric disorders.

Animals↗

PubMed2005

Autoradiographic mapping of dopamine-D2/D3 receptor stimulated [35S]GTPgammaS binding in the human brain.

Agonist stimulated [35S]guanosine 5'-gamma-thiotriphosphate ([35S]GTPgammaS) binding autoradiography was established for the examination of dopamine-D2/D2 receptors in human brain sections. The distribution of G proteins activated by dopamine-D2/D3 receptors was studied in whole hemisphere cryosections. Dopamine stimulated [35S]GTPgammaS binding in brain regions with high densities of dopamine D2-like receptors, i.e. putamen (23 +/- 2%, mean +/- SEM,% stimulation over basal binding), caudate (20 +/- 0%) and substantia nigra (22 +/- 2%), but also in regions with lower receptor densities such as amygdala (17 +/- 8%), hippocampus (16 +/- 6%), anterior cingulate (13 +/- 3%), and thalamus (12 +/- 2%). Dopamine stimulated [35S]GTPgammaS binding to significantly higher levels in the dorsal than in the ventral part of the striatum. Dopamine caused low or very low stimulation in all cortical areas. Raclopride, a selective D2/D3 receptor antagonist, potently inhibited dopamine stimulated [35S]GTPgammaS binding, whereas R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH23390), a selective D1 antagonist, did not block the [35S]GTPgammaS binding response stimulated by dopamine. Hence, the stimulatory effect of dopamine was primarily mediated by D2/D3 receptors. Quinpirole stimulated [35S]GTPgammaS binding in the same regions as dopamine. The maximal level of stimulation induced by dopamine and quinpirole was not significantly different. The present study demonstrates that agonist stimulated [35S]GTPgammaS binding autoradiography could be a suitable technique for the examination of dopamine-D2/D3 receptors in the human brain. This functional assay could provide useful new information about dopamine receptor/G protein coupling in the postmortem human brain, and reveal possible disease related alterations of the interaction between D2/D3 receptors and G proteins.

Adult↗

PubMed2004

[11C]vinpocetine: a prospective peripheral benzodiazepine receptor ligand for primate PET studies.

Vinpocetine, a synthetic derivative of the Vinca minor alkaloid vincamine, is a widely used drug in neurological practice. We tested the hypothesis that vinpocetine binds to peripheral benzodiazepine binding sites (PBBS) and is therefore a potential ligand of PBBS. Positron emission tomography (PET) measurements in two cynomolgous monkeys showed that pretreatment with vinpocetine markedly reduced the brain uptake of [11C]PK11195, a known PBBS radioligand. On the other hand, whereas pretreatment with PK11195 increased the brain uptake of [11C]vinpocetine due to the blockade of PBBS in the periphery, it significantly reduced the binding potential (BP) values of [11C]vinpocetine in the whole brain and in individual brain structures to PK11195. These findings indicate that, whereas the two ligands have different affinities to PBBS, vinpocetine is a potent ligand of PBBS, which in turn suggests that the pharmacological activity of vinpocetine may involve the regulation of glial functions.

Animals↗

PubMed2004

Feature uncertainty: a novel test to probe prefrontal dysfunction in unaffected siblings of schizophrenia patients.

Previous studies indicated that neuropsychological impairments are potential endophenotypes of schizophrenia. However, the sensitivity of these procedures is not sufficient and their brain substrates are poorly defined. The aim of this study was to measure the behavioral performance of siblings of schizophrenia patients and controls on a novel feature uncertainty (FU) task that selectively activates dorsal anterior cingulate cortex relative to orientation (OR) and spatial frequency (SF) discrimination. During the FU task, two subsequent sinusoidal gratings are presented and participants are asked to remember both the OR and SF of the gratings. After the disappearance of the gratings, a color cue signifies the perceptual dimension (OR or SF) to discriminate. Results revealed that the siblings of schizophrenia patients (n = 25) showed a selective deficit on the FU task as compared with controls (n = 20). The FU deficit was more severe than that found on neuropsychological tests of executive functions, psychomotor speed, and verbal memory. These results suggest that anterior cingulate dysfunction is a potential endophenotype of schizophrenia.

Adult↗

PubMed2004

Smelling human sex hormone-like compounds affects face gender judgment of men.

Although strong cross-sensory interactions between visual, tactile and auditory modalities have already been shown, we know little about how chemosensory information affects processing in other sensory modalities. We studied whether smelling gender-specific odorous sex hormone-like steroids: 5-alpha-androgenst-16-en-3-one (androgen) or oestra-1, 3, 5 (10), 16-tetraen-3-ol (estrogen) can bias face gender discrimination. We found that, as a result of inhalation of androgen, men perceive faces to be more masculine as compared to when they are exposed to estrogen. Our results provide evidence for specific cross-sensory effects of the gender-specific chemosensory cues on the categorization of visual face gender.

Adult↗

PubMed2004

Feature uncertainty activates anterior cingulate cortex.

In visual discrimination tasks, the relevant feature to discriminate is defined before stimulus presentation. In feature uncertainty tasks, a cue about the relevant feature is provided after stimulus offset. We used (15)O-butanol positron emission tomography (PET) in order to investigate brain activation during a feature uncertainty task. There was greater activity during the feature uncertainty task, compared with stimulus detection and discrimination of orientation and spatial frequency, in the lateral and medial prefrontal cortex, the cuneus, superior temporal and inferior parietal cortex, cortical motor areas, and the cerebellum. The most robust and consistent activation was observed in the dorsal anterior cingulate cortex (Brodmann area 32; x = 0 y = 16, z = 40). The insula, located near the claustrum (x = -38, y = 8, z = 4), was activated during the discrimination tasks compared with the feature uncertainty condition. These results suggest that the dorsal anterior cingulate cortex is important in feature uncertainty conditions, which include divided attention, expectancy under uncertainty, and cognitive monitoring.

Adult↗

PubMed2004

PET evaluation of novel radiofluorinated reboxetine analogs as norepinephrine transporter probes in the monkey brain.

(S,S)-2-(alpha-(2-Fluoromethoxyphenoxy)benzyl)morpholine ((S,S)-FMeNER) was found to be a selective high-affinity ligand for the norepinephrine transporter (NET). (S,S)-FMeNER) was labeled with fluorine-18 (t1/2 = 109.8 min) by O-fluoromethylation of desfluoromethoxy-(S,S)-FMeNER with [18F]bromofluoromethane. An analog, di-deuterated in the fluoromethoxy group ((S,S)-FMeNER-D2), was similarly labeled with di-deutero-[18F]bromofluoromethane. These two new radioligands were obtained in radiochemical purities greater than 98% and with specific radioactivities ranging from 111-185 GBq/micromol at the end of synthesis (75 min). After intravenous injection of (S,S)-[18F]FMeNER into cynomolgus monkey, PET examination with the head in the field of view revealed skull-bound radioactivity, contaminating images of the brain, and indicated fast defluorination of the radioligand. Defluorination was much reduced in similar PET experiments with (S,S)-[18F]FMeNER-D2. Ratios of radioactivity in the lower brainstem, mesencephalon, thalamus, and temporal cortex to striatum obtained with (S,S)-[18F]FMeNER-D2 at 160 min after i.v. injection were 1.5, 1.6, 1.3, and 1.5, respectively. In another PET experiment, pretreatment of the monkey with the selective NET inhibitor, desipramine, decreased the radioactivity ratios in all examined regions to near unity (e.g., to a ratio of 1.03 in mesencephalon). Labeled metabolites of (S,S)-[18F]FMeNER-D2 or (S,S)-[18F]FMeNER found in plasma were all more polar than the parent radioligand. In vitro autoradiography of (S,S)-[18F]FMeNER-D2 on post-mortem human brain cryosections furthermore showed specific binding to NET in the locus coeruleus and thalamus. (S,S)-[18F]FMeNER-D2 is the first useful radiofluorinated ligand for imaging brain NET in monkey in vivo and is superior to (S,S)-[11C]MeNER because a specific binding peak equilibrium is obtained during the PET experiment at a lower noise level.

Animals↗