Biomedical subjects

Kjell Någren

Publications and source records attributed to Kjell Någren.

13 recordsLinked to original sources

PubMed2003

Radiolabeling and biodistribution of methyl 2-(methoxycarbonyl)-2-(methylamino) bicyclo[2.1.1] -hexane -5-carboxylate, a potential neuroprotective drug.

Methyl 2-(methoxycarbonyl) -2-(methylamino) bicyclo[2.1.1] -hexane -5-carboxylate (MMMHC) is developed as a potential neuroprotective drug. It was labeled with C-11 from the desmethyl precursor methyl 2-(methoxycarbonyl)-2-amino bicyclo[2.1.1]-hexane-5-carboxylate with [11C]methyl triflate in acetone solution at 60 degrees C with labeling yield of 69% and with radiochemical purity of >99%. Positron Emission Tomography (PET) studies in a normal rat showed that Methyl 2-(methoxycarbonyl)-2-([11C]methylamino)bicyclo[2.1.1]-hexane-5-carboxylate ([11C] MMMHC) accumulated mainly in the cortical brain areas after iv administration. Frontal cortex/cerebellum ratios in a rat brain were 8.0/6.0, 6.8/4.2, 6.3/4.3, 5.5/4.2 and 5.2/4.5 percent of the injected dose in 100 ml at 2 min, 5 min, 10 min, 20 min and 40 min respectively after i.v. injection. During 20-40 min, 2.9+/-0.4% of the total activity stayed in the brain. These results showed that MMMHC could be labeled with C-11 with high yield, and it passed the brain-blood barrier and accumulated in several brain regions.

Animals↗

PubMed2003

Striatal dopamine D1 and D2 receptors in burning mouth syndrome.

Animal studies have indicated that the nigrostriatal dopaminergic system is involved in central pain modulation. In a recent positron emission tomography (PET) study, we demonstrated presynaptic dysfunction of the nigrostriatal dopaminergic pathway in burning mouth syndrome, which is a chronic pain state. The objective of the present study was to examine striatal dopamine D1 and D2 receptors in these patients. We used 11C-NNC 756 and 11C-raclopride to study D1 and D2 receptor binding in a PET study in ten burning mouth patients and 11 healthy controls. Patients underwent a structured psychiatric evaluation and an electrophysiological test for the excitability of the blink reflex. The striatal uptake of 11C-NNC 756 did not differ between patients and controls. In a voxel-level analysis, the uptake of 11C-raclopride was statistically significantly higher in the left putamen in burning mouth patients (corrected P-value 0.038 at cluster-level). In the region of interest analysis, the D1/D2 ratio was 7.7% lower in the right putamen (0.64+/-0.04 vs. 0.69+/-0.04, P=0.01) and 6.4 % lower in the left putamen (0.65+/-0.05 vs. 0.70+/-0.05, P=0.05) when compared to controls. Increased 11C-raclopride uptake and the subsequent decrease in the D1/D2 ratio may indicate a decline in endogenous dopamine levels in the putamen in burning mouth patients.

Adult↗

PubMed2002

Synthesis, radiolabeling and preliminary biological evaluation of radiolabeled 5-methyl-6-nitroquipazine, a potential radioligand for the serotonin transporter.

5-Methyl-6-nitroquipazine, a novel analogue of the potent and selective serotonin transporter inhibitor 6-nitroquipazine was synthesized and radiolabeled with tritium and the positron emitter carbon-11. [3H]5-methyl-6-nitroquipazine was found to have a K(d)=51+/-7 pM. The high affinity and the facile labeling of [11C]5-methyl-6-nitroquipazine makes it a promising radioligand for visualization of the serotonin transporter with positron emission tomography.

Animals↗

PubMed2002

Uptake of [N-methyl-11C]alpha-methylaminoisobutyric acid in untreated head and neck cancer studied by PET.

Amino acid transport system A is expressed strongly in neoplastic cells. [ N-methyl-(11)C]alpha-Methylaminoisobutyric acid ((11)C-MeAIB) is a recently developed tracer for PET studies on system A amino acid transport. (11)C-MeAIB is a metabolically stable amino acid analogue which is transported from plasma into the tissue by system A. This study evaluated the kinetics of (11)C-MeAIB uptake from plasma into tumour tissue and normal tissues in 13 patients with untreated head and neck cancer. (11)C-MeAIB uptake in tumour was compared with histological grade and proliferative activity. Tracer uptake was quantitated by calculating the standardised uptake values (SUVs) and the kinetic influx constants ( K(i)) using graphical analysis. All tumours accumulated (11)C-MeAIB and were visualised clearly. In the graphical analysis, linear plots were achieved; the mean K(i) value of tumour was 0.056+/-0.026 min(-1), and the mean SUV was 6.1+/-2.7. A close correlation between graphically obtained K(i) and semi-quantitative SUV in tumours was found ( r=0.887, P=0.00005). We could not demonstrate a correlation between the uptake of (11)C-MeAIB and the grade of malignancy or the proliferative index, as assessed using Ki-67 immunohistochemical assay. Head and neck cancer can be effectively imaged with (11)C-MeAIB PET. (11)C-MeAIB showed active and rapid transport into tumour tissue and salivary glands. Further studies on the applicability of (11)C-MeAIB PET for radiation treatment planning in the head and neck region and the regulation of system A amino acid transport under different metabolic states are warranted.

Adult↗

PubMed2002

Ketamine does not decrease striatal dopamine D2 receptor binding in man.

RATIONALE: A glutamate-dopamine interaction has been implicated in the psychosis-like effects of glutamate N-methyl- D-aspartate (NMDA) receptor antagonists, such as phencyclidine and ketamine. However, recent imaging studies addressing striatal glutamate-dopamine interaction directly in vivo in man have been controversial. OBJECTIVES: To examine whether the NMDA receptor antagonist ketamine in high subanesthetic concentrations decreases striatal [(11)C]raclopride binding potential in man. To further evaluate whether changes in striatal [(11)C]raclopride binding are associated with ketamine-induced behavioral effects. METHODS: The effect of computer-driven subanesthetic ketamine infusion on striatal dopamine release was studied in healthy male subjects using a controlled study design. Dopamine release was studied using positron emission tomography and the [(11)C]raclopride displacement paradigm. A conventional region of interest-based analysis and voxel-based analysis were applied to the positron emission tomography data. RESULTS: The average plasma ketamine concentration was 293+/-29 ng/ml. Ketamine did not alter striatal [(11)C]raclopride binding. Ketamine induced typical behavioral effects, such as hallucinations but there was no correlation between these effects and displacement of [(11)C]raclopride binding. CONCLUSIONS: This controlled study indicates that ketamine does not decrease striatal [(11)C]raclopride binding. Striatal dopamine release is of minor importance in the psychosis-like effects of ketamine.

Adult↗

PubMed2002

Metabolic characterization of childhood brain tumors: comparison of 18F-fluorodeoxyglucose and 11C-methionine positron emission tomography.

BACKGROUND: Positron emission tomography (PET) scans of primary brain tumors were performed in pediatric patients to examine whether metabolic characteristics could be used as an index of clinical aggressiveness. METHODS: Twenty-seven pediatric patients with untreated primary central nervous system neoplasms were studied with PET scans using 2-[(18)F] fluoro-2-deoxy-D-glucose (FDG) and/or L-[methyl-(11)C] methionine (MET). Metabolic characteristics as assessed with FDG and MET standardized uptake values (SUV) and SUV-to-normal brain ratios were compared with histopathology and selected histochemical features such as proliferation activity (Ki-67(MIB-1)) and apoptotic, vascular, and cell density indices. The median followup time was 43 months. RESULTS: The accumulation of both FDG and MET was significantly higher in high-grade than in low-grade tumors, but a considerable overlap was found. The accumulation of both tracers was associated positively with age. High-grade tumors showed higher proliferative activity and vascularity than the low-grade tumors. In univariate analysis, FDG-PET, MET-PET, and apoptotic index were independent predictors of event-free survival. CONCLUSION: We found that both FDG and MET uptake in pediatric brain tumors are associated with malignancy grade. However, no clear limits of SUVs and SUV-to-normal brain ratios can be set between low-grade and high-grade tumors, which makes the assessment of malignancy grade using metabolic imaging with PET scan difficult in individual cases. Although FDG-PET and MET-PET do not compensate for histopathologic evaluation, they may give valuable additional information especially if invasive procedures to obtain histopathologic samples are not feasible.

Adolescent↗

PubMed2002

Amino acid uptake in the skeletal muscle measured using [11C]methylaminoisobutyrate (MEAIB) and PET.

An amino acid analogue, [(11)C]MeAIB, recently introduced for oncological positron emission tomography (PET) studies, is a highly selective substrate for insulin-sensitive amino acid transport system A. The aim of this study was to study the uptake kinetics of [(11)C]MeAIB in skeletal muscle in the fasting state and during insulin stimulation. Two dynamic PET studies were carried out in 11 healthy subjects, once in the fasting state and once during euglycaemic hyperinsulinaemia (serum insulin 67+/-12 mU l(-1)). Graphical analysis was used to calculate the fractional [(11)C]MeAIB uptake rate ( K(i)). Amino acid uptake was estimated by multiplying K(i) by the serum amino acid concentration. After tracer injection, rapid uptake in muscle tissue was detected both in the fasting state and during insulin stimulation and femoral muscles were clearly visualised in both studies. In the graphical analysis, the volume of distribution of [(11)C]MeAIB plotted against normalised plasma time yielded a linear curve (the slope of which = K(i)). The fractional [(11)C]MeAIB uptake rate ( K(i)) in the femoral muscle regions increased from 0.0070+/-0.0018 min(-1) (mean+/-SD) in the fasting state to 0.0079+/-0.0020 min(-1) ( P<0.05) during insulin stimulation. When compared with the fasting state, serum total amino acid concentration decreased from 2.49+/-0.22 to 2.16+/-0.18 mmol l(-1) ( P<0.0001) and the serum concentration of six amino acids typically using system A for their transport decreased from 0.72+/-0.1 to 0.63+/-0.07 mmol l(-1) ( P=0.0001) during hyperinsulinaemia. The calculated skeletal muscle total amino acid uptake and the uptake of the six amino acids typically using system A were similar in the fasting state and during insulin clamp (17.1+/-3.2 vs 17.7+/-3.7 micro mol kg(-1) min(-1), NS, and 5.0+/-1.3 vs 5.0+/-1.4 micro mol kg(-1) min(-1), NS, respectively). The uptake rates correlated with perfusion both in the fasting state and during hyperinsulinaemia ( P<0.05). [(11)C]MeAIB PET appears to be a feasible method for measurement of amino acid uptake in human skeletal muscle. As a tracer that is not metabolised in the tissues, [(11)C]MeAIB provides simple modelling and robust data analysis and thus provides a means to investigate amino acid uptake into muscle tissue in various disease conditions known to affect protein metabolism.

Amino Acids↗

PubMed2002

Mu-receptor agonism with alfentanil increases striatal dopamine D2 receptor binding in man.

Animal studies indicate that mu-opioids indirectly modulate neurotransmission in the nigrostriatal dopaminergic pathway. We used positron emission tomography (PET) to study the effects of alfentanil (a mu-opioid receptor agonist) on striatal dopamine D2 receptor binding in eight healthy male volunteers. D2 receptor binding was determined by using [(11)C]raclopride as radioligand. Each subject underwent two PET sessions on the same day, the first without the drug (control) and the second during alfentanil infusion. Alfentanil was administered as target-controlled infusion to maintain pseudo steady-state plasma concentration of 80 ng/ml throughout the PET session. A freeze lesion model was used for pain testing at the end of both PET sessions. A mechanical pain stimulus of 5 N was rated by the subjects using a visual analog scale. Regions of interest for the putamen, caudate nucleus, and cerebellum were drawn on MRI images and transferred to PET images. Alfentanil increased the binding potential of [(11)C]raclopride in the putamen by 6.0% (P = 0.04) and in the caudate nucleus by 7.4% (P = 0.008). Alfentanil caused a small reduction in respiratory rate (P = 0.046) and oxygen saturation (P < 0.001), and a moderate consistent increase in end-tidal CO(2) (P < 0.001). Pain scores were significantly smaller after alfentanil PET scan (median VAS 9 (0-42) vs. 23.5 (15-52), P = 0.008). These results indicate that pharmacologically relevant concentrations of alfentanil increase D2 dopamine receptor binding in the striatum in man. This increase is assumed to reflect reduced dopamine release.

Adult↗

PubMed2002

Dopamine D2 receptor binding in the human brain is associated with the response to painful stimulation and pain modulatory capacity.

The pain modulatory role of dopamine D2 receptors of the human forebrain was studied by determining the association between dopamine D2 receptor binding potential and the response to experimental pain. Nineteen healthy male volunteers participated in a dopamine D2 receptor positron emission tomography study. The extrastriatal regions of interest studied with [11C]FLB 457 as radioligand (n = 11) were the anterior cingulum, the medial and lateral thalamus, the medial and lateral frontal cortex, and the medial and lateral temporal cortex. The striatal regions of interest studied with [11C]raclopride (n = 8) were the caudate nucleus and the putamen. The latency to the ice water-induced cold pain threshold and tolerance were determined in a separate psychophysical test session. Moreover, the cutaneous heat pain threshold and its elevation by concurrent cold pain in the contralateral hand were determined in each subject. Cold pain threshold was inversely correlated with D2 binding potential in the right putamen and the cold pain tolerance was inversely correlated with D2 binding potential in the right medial temporal cortex. The magnitude of heat pain threshold elevation induced by concurrent cold pain was directly correlated with D2 binding potential in the left putamen. Other correlations of D2 binding potentials in varying brain regions with sensory responses were not significant. A psychophysical control study (n = 10) showed that cold pain responses were identical in the right and left hand. The results indicate that dopamine D2 receptor binding potential in the human forebrain, particularly in the striatum, may be an important parameter in determining the individual cold pain response and the potential for central pain modulation. Accordingly, an individual with only few available D2 receptors in the forebrain is likely to have a high tonic level of pain suppression, combined with a low capacity to recruit more (dopaminergic) central pain inhibition by noxious conditioning stimulation.

Adult↗

PubMed2002

PET examination of [(11)C]5-methyl-6-nitroquipazine, a radioligand for visualization of the serotonin transporter.

Radiohalogenated 5-halo-6-nitroquipazine analogues have been shown to be potential radioligands for visualization of the serotonin transporter (5-HTT) with PET and SPECT. In the present study a methylated analogue, 5-methyl-6-nitroquipazine (MNQP), was radiolabeled with carbon-11 in a two step reaction via a palladium catalyzed cross coupling reaction between N-t-BOC-protected 5-tributylstannyl-6-nitroquipazine and [(11)C]methyl iodide as key step. [(11)C]MNQP was examined in the cynomolgus monkey brain with positron emission tomography (PET) and the appearance of labeled metabolites in monkey plasma was measured with gradient HPLC. Radioactivity increased continuously in all brain regions during the 90 minutes acquisition time. Highest accumulation of radioactivity was observed in the thalamus and brainstem, regions with a known high density of 5-HTT. The calculated ratios between the thalamus and brainstem to the 5-HTT poor cerebellum were 1.5 and 1.3-1.4, respectively, 80 minutes after radioligand injection. Pretreatment with citalopram prior to the PET measurement markedly reduced the binding in the thalamus and the brainstem. At 15 and 30 minutes after injection of [(11)C]MNQP approximately 90% and 60%, respectively, of radioactivity in plasma represented unchanged radioligand. The slow kinetics and moderate ratios recorded however, may limit its use as a PET radioligand for quantitative studies of the serotonin transporter with PET.

Animals↗

PubMed2002

Age-related loss of extrastriatal dopamine D(2) -like receptors in women.

Positron emission tomography (PET) studies have indicated that the in vivo availability of dopamine D(2) -like receptors declines with age in the human brain. Most of the studies have been carried out with healthy male subjects, or with subject groups containing both sexes. The authors have recently demonstrated that the availability of D(2) -like receptors in the frontal cortex is higher in women than in men. The present study was aimed to further examine this phenomenon. Thirty-seven healthy women (age range 22-78 years) were examined with PET and [(11) C]FLB 457, a high-affinity tracer for the extrastriatal D(2) -like receptors. A negative relationship between age and dopamine D(2) -like receptor availability was seen in the frontal cortex (decrease of 12% per decade of life), the temporal cortex (9%) and the thalamus (6%). A non-linear s-shape association explained the relationship only in the frontal cortex, while in other regions the association was linear. Neither oestradiol nor progesterone levels had a significant relationship with the [(11) C]FLB 457 uptake in any of the brain regions studied after the effect of age was partialled out. The results indicate that: (i) the extrastriatal D(2) -like receptor availability decreases with age in healthy women with the fastest rate in the frontal cortex and with the overall rate close to the rate reported in healthy men; (ii) around midlife (age 40-60 years) in women, the frontal receptor decline plateaus while the decline continues to be linear in other extrastriatal brain regions; and (iii) serum oestradiol or progesterone levels are not associated with cortical or thalamic D(2) -like receptor availability in women. The results may prove to be important in studies where the biochemical basis of clinical sex differences is examined in patients with dopamine-related neuropsychiatric disorders.

Adult↗

PubMed2002

Regional effects of donepezil and rivastigmine on cortical acetylcholinesterase activity in Alzheimer's disease.

Donepezil and rivastigmine are acetylcholinesterase (AChE) inhibitors used to improve cholinergic neurotransmission and cognitive function in Alzheimer's disease (AD). This study examined direct effects of these drugs on AChE activity in the frontal, temporal, and parietal cortices in AD. Six AD patients were scanned with positron emission tomography before and after 3 months of treatment with donepezil (10 mg/day), and five AD patients were scanned before and after 3 to 5 months of treatment with rivastigmine (9 mg/day). Healthy unmedicated controls were imaged twice to evaluate the reproducibility of the method. A specific AChE tracer, [methyl-11C]N-methyl-piperidyl-4-acetate, and a 3D positron emission tomography system with MRI coregistration were used for imaging. Treatment with donepezil reduced the AChE activity (k3 values) in the AD brain by 39% in the frontal (p < 0.001, Bonferroni corrected), 29% in the temporal (p = 0.02, corrected) and 28% in the parietal cortex (p = 0.05, corrected). The corresponding levels of inhibition for rivastigmine were 37% (p = 0.003, corrected), 28% (p = 0.03, uncorrected) and 28% (p = 0.05, corrected). When the treatment groups were combined, the level of AChE inhibition was significantly greater in the frontal cortex compared to the temporal cortex (p = 0.03, corrected). The test-retest analysis with healthy subjects indicated good reproducibility for the method, with a nonsignificant 0% to 7% intrasubject variability between scans. The present study provides first evidence for the effect of rivastigmine on cortical AChE activity. Our results indicate that the pooled effects of donepezil and rivastigmine on brain AChE are greater in the frontal cortex compared to the temporal cortex in AD. This regional difference is probably related to the prominent temporoparietal reduction of AChE in AD. We hypothesize that the clinical improvement in behavioral and attentional symptoms of AD due to AChE inhibitors is associated with the frontal AChE inhibition.

Acetylcholinesterase↗

PubMed2002

Exercise training in chronic heart failure: beneficial effects on cardiac (11)C-hydroxyephedrine PET, autonomic nervous control, and ventricular repolarization.

UNLABELLED: Abnormalities of autonomic nervous function are associated with a poor prognosis of patients with chronic heart failure (CHF). We studied the effects of a 6-mo exercise training program on Q-T interval dispersion, heart rate and blood pressure variability, baroreflex sensitivity, myocardial blood flow (MBF), and presynaptic sympathetic innervation in 13 patients with New York Heart Association class II-III heart failure. METHODS: MBF was measured with the H(2)(15)O and C(15)O technique. Cardiac presynaptic innervation was studied by (11)C-hydroxyephedrine (HED) retention assessed with PET. Heart rate and blood pressure variability and baroreflex sensitivity were tested with the phenylephrine method. All studies were performed before and after a 6-mo exercise training program. The exercise capacity was determined by spiroergometry, and Q-T dispersion was measured from a standard 12-lead electrocardiogram. RESULTS: Q-T dispersion was reduced after the training period (mean +/- SEM, from 52 +/- 5 to 36 +/- 5 ms [P = 0.01]). Global (11)C-HED retention improved from 0.228 +/- 0.099 to 0.263 +/- 0.066 s(-1) (P < 0.05). Global MBF was not affected by training, but MBF increased in areas of low initial perfusion in patients with coronary artery disease (from 0.382 +/- 0.062 to 0.562 +/- 0.083 mL/g/min [P < 0.005]). The high-frequency spectrum and total R-R interval variability increased (from 4.53 +/- 0.30 to 5.02 +/- 0.36 ms(2) [P < 0.05] and from 3.60 +/- 0.34 to 4.31 +/- 0.37 ms(2) [P < 0.005], respectively). Both changes correlated significantly with the observed change in (11)C-HED retention. There was a significant reduction of total and a near-significant reduction of low-frequency (LF) systolic blood-pressure (SBP) variability (from 4.89 +/- 1.03 to 3.18 +/- 0.48 [P < 0.05] and from 2.79 +/- 0.38 to 1.76 +/- 0.24 [P = 0.059], respectively). The decrease in LF SBP variability correlated inversely with the enhancement of (11)C-HED retention (r = -0.66; P < 0.05). Baroreflex sensitivity increased from 5.83 +/- 0.82 to 10.15 +/- 1.66 ms/mm Hg (P < 0.05). CONCLUSION: Exercise training induces beneficial changes in functional and imaging measures of cardiovascular autonomic nervous control. These observations point to a training-induced shift toward normalization of the compensatory autonomic nervous imbalance in CHF.

Autonomic Nervous System↗