Dimethyl fumarate decreases short-term but not long-term inflammation in a focal EAE model of neuroinflammation.

BACKGROUND: Dimethyl fumarate (DMF) is an oral immunomodulatory drug used in the treatment of autoimmune diseases. Here, we sought to study whether the effect of DMF can be detected using positron emission tomography (PET) targeting the 18-kDa translocator protein (TSPO) in the focal delayed-type hypersensitivity rat model of multiple sclerosis (fDTH-EAE). The rats were treated orally twice daily from lesion activation (day 0) with either vehicle (tap water with 0.08% Methocel, 200 µL; control group n = 4 (3 after week four)) or 15 mg/kg DMF (n = 4) in 0.08% aqueous Methocel (200 µL) for 8 weeks. The animals were imaged by PET using the TSPO tracer [18F]GE-180 in weeks 0, 1, 2, 4, 8, and 18 following lesion activation, and the non-displaceable binding potential (BPND) was calculated. Immunohistochemical staining for Iba1, CD4, and CD8 was performed in week 18, and in separate cohorts of animals, following 2 or 4 weeks of treatment. RESULTS: Using the fDTH-EAE model, DMF reduced the [18F]GE-180 BPND in the DMF-treated animals compared to control animals after 1 week of treatment (two-tailed unpaired t test, p = 0.031), but not in weeks 2, 4, 8, or 18 when imaged in vivo by PET. Immunostaining for Iba1 showed that DMF had no effect on the perilesional volume or the core lesion volume after 2 or 4 weeks of treatment, or at 18 weeks. However, the optical density (OD) measurements of CD4+ staining showed reduced OD in the lesions of the treated rats. CONCLUSIONS: DMF reduced the microglial activation in the fDTH-EAE model after 1 week of treatment, as detected by PET imaging of the TSPO ligand [18F]GE-180. However, over an extended time course, reduced microglial activation was not observed using [18F]GE-180 or by immunohistochemistry for Iba1+ microglia/macrophages. Additionally, DMF did affect the infiltration of CD4+ and CD8+ T-lymphocytes at the fDTH-EAE lesion.

Cessation of anti-VLA-4 therapy in a focal rat model of multiple sclerosis causes an increase in neuroinflammation.

BACKGROUND: Positron emission tomography (PET) can be used for in vivo evaluation of the pathology associated with multiple sclerosis. We investigated the use of longitudinal PET imaging and the 18-kDa translocator protein (TSPO) binding radioligand [18F]GE-180 to detect changes in a chronic multiple sclerosis-like focal delayed-type hypersensitivity experimental autoimmune encephalomyelitis (fDTH-EAE) rat model during and after anti-VLA-4 monoclonal antibody (mAb) treatment. Thirty days after lesion activation, fDTH-EAE rats were treated with the anti-VLA-4 mAb (n = 4) or a control mAb (n = 4; 5 mg/kg, every third day, subcutaneously) for 31 days. Animals were imaged with [18F]GE-180 on days 30, 44, 65, 86 and 142. Another group of animals (n = 4) was used for visualisation the microglia with Iba-1 at day 44 after a 2-week treatment period. RESULTS: After a 2-week treatment period on day 44, there was a declining trend (p = 0.067) in [18F]GE-180-binding in the anti-VLA-4 mAb-treated animals versus controls. However, cessation of treatment for 4 days after a 31-day treatment period increased [18F]GE-180 binding in animals treated with anti-VLA-4 mAb compared to the control group (p = 0.0003). There was no difference between the groups in TSPO binding by day 142. CONCLUSIONS: These results demonstrated that cessation of anti-VLA-4 mAb treatment for 4 days caused a transient rebound increase in neuroinflammation. This highlights the usefulness of serial TSPO imaging in the fDTH-EAE model to better understand the rebound phenomenon.

Comparative effects of dexmedetomidine, propofol, sevoflurane, and S-ketamine on regional cerebral glucose metabolism in humans: a positron emission tomography study.

INTRODUCTION: The highly selective α2-agonist dexmedetomidine has become a popular sedative for neurointensive care patients. However, earlier studies have raised concern that dexmedetomidine might reduce cerebral blood flow without a concomitant decrease in metabolism. Here, we compared the effects of dexmedetomidine on the regional cerebral metabolic rate of glucose (CMRglu) with three commonly used anaesthetic drugs at equi-sedative doses. METHODS: One hundred and sixty healthy male subjects were randomised to EC50 for verbal command of dexmedetomidine (1.5 ng ml-1; n=40), propofol (1.7 µg ml-1; n=40), sevoflurane (0.9% end-tidal; n=40) or S-ketamine (0.75 µg ml-1; n=20) or placebo (n=20). Anaesthetics were administered using target-controlled infusion or vapouriser with end-tidal monitoring. 18F-labelled fluorodeoxyglucose was administered 20 min after commencement of anaesthetic administration, and high-resolution positron emission tomography with arterial blood activity samples was used to quantify absolute CMRglu for whole brain and 15 brain regions. RESULTS: At the time of [F18]fluorodeoxyglucose injection, 55% of dexmedetomidine, 45% of propofol, 85% of sevoflurane, 45% of S-ketamine, and 0% of placebo subjects were unresponsive. Whole brain CMRglu was 63%, 71%, 71%, and 96% of placebo in the dexmedetomidine, propofol, sevoflurane, and S-ketamine groups, respectively (P<0.001 between the groups). The lowest CMRglu was observed in nearly all brain regions with dexmedetomidine (P<0.05 compared with all other groups). With S-ketamine, CMRglu did not differ from placebo. CONCLUSIONS: At equi-sedative doses in humans, potency in reducing CMRglu was dexmedetomidine>propofol>ketamine=placebo. These findings alleviate concerns for dexmedetomidine-induced vasoconstriction and cerebral ischaemia. CLINICAL TRIAL REGISTRATION: NCT02624401.

Increased insulin-stimulated glucose uptake in both leg and arm muscles after sprint interval and moderate-intensity training in subjects with type 2 diabetes or prediabetes.

We investigated the effects of sprint interval training (SIT) and moderate-intensity continuous training (MICT) on glucose uptake (GU) during hyperinsulinemic euglycemic clamp and fatty acid uptake (FAU) at fasting state in thigh and arm muscles in subjects with type 2 diabetes (T2D) or prediabetes. Twenty-six patients (age 49, SD 4; 10 women) were randomly assigned into two groups: SIT (n=13) and MICT (n=13). The exercise in the SIT group consisted of 4-6×30 s of all-out cycling with 4- minute recovery and in the MICT group 40- to 60- minute cycling at 60% of VO2peak . Both groups completed six training sessions within two weeks. GU and FAU were measured before and after the intervention with positron emission tomography in thigh (quadriceps femoris, QF; and hamstrings) and upper arm (biceps and triceps brachii) muscles. Whole-body insulin-stimulated GU increased significantly by 25% in both groups, and this was accompanied with significantly increased insulin-stimulated GU in all thigh and upper arm muscles and significantly increased FAU in QF. Within QF, insulin-stimulated GU improved more by SIT than MICT in rectus femoris (P = .01), but not differently between the training modes in the other QF muscles. In individuals with T2D or prediabetes, both SIT and MICT rapidly improve insulin-stimulated GU in whole body and in the thigh and arm muscles as well as FAU in the main working muscle QF. These findings highlight the underused potential of exercise in rapidly restoring the impaired skeletal muscle metabolism in subjects with impaired glucose metabolism.

Positron emission tomography and [18F]BPA: a perspective application to assess tumour extraction of boron in BNCT.

Positron emission tomography (PET) has become a key imaging tool in clinical practice and biomedical research to quantify and study biochemical processes in vivo. Physiologically active compounds are tagged with positron emitters (e.g. (18)F, (11)C, (124)I) while maintaining their biological properties, and are administered intravenously in tracer amounts (10(-9)-10(-12)M quantities). The recent physical integration of PET and computed tomography (CT) in hybrid PET/CT scanners allows a combined anatomical and functional imaging: nowadays PET molecular imaging is emerging as powerful pharmacological tool in oncology, neurology and for treatment planning as guidance for radiation therapy. The in vivo pharmacokinetics of boron carrier for BNCT and the quantification of (10)B in living tissue were performed by PET in the late nineties using compartmental models based on PET data. Nowadays PET and PET/CT have been used to address the issue of pharmacokinetic, metabolism and accumulation of BPA in target tissue. The added value of the use of L-[(18)F]FBPA and PET/CT in BNCT is to provide key data on the tumour extraction of (10)B-BPA versus normal tissue and to predict the efficacy of the treatment based on a single-study patient analysis. Due to the complexity of a binary treatment like BNCT, the role of PET/CT is currently to design new criteria for patient enrolment in treatment protocols: the L-[(18)F]BPA/PET methodology could be considered as an important tool in newly designed clinical trials to better estimate the concentration ratio of BPA in the tumour as compared to neighbouring normal tissues. Based on these values for individual patients the decision could be made whether BNCT treatment could be advantageous due to a selective accumulation of BPA in an individual tumour. This approach, applicable in different tumour entities like melanoma, glioblastoma and head and neck malignancies, make this methodology as reliable prognostic and therapeutic indicator for patient undergoing BNCT.

Excitation functions of 3He- and alpha-particle induced nuclear reactions on natSb for production of medically relevant 123I and 124I radioisotopes.

Excitation functions were measured using the stacked foil irradiation technique from threshold energies to 28 MeV for (3)He- and to 21 MeV for alpha-particle induced nuclear reactions on natural antimony leading to the formation of (121,123,124)I radioisotopes. The measured excitation functions were compared with the contradicting results of the earlier investigations found in the literature and with the curves predicted by the ALICE-IPPE and EMPIRE-II codes. Integral yields were also calculated and compared with the experimental thick target yields reported in the literature.

Imaging of tumor hypoxia to predict treatment sensitivity.

Non-invasive detection of tumor hypoxia using radiolabeled 2-nitroimidazoles has been a major effort during the last two decades. Recent years have witnessed the introduction of several new compounds which are chemically related to [(18)F]fluoromisonidazole (FMISO) but show slight but distinct differences in biodistribution and metabolic clearance. Although [(18)F]FMISO has shown clinical potential it suffers from suboptimal oxygen dependent tissue contrast and newer agents seek to improve this essential feature. The limited data on other interesting tracers keeps the investigators busy at demonstrating the potential advantages over [(18)F]FMISO while efforts should start to concentrate on proving the clinical significance of such techniques in the form of outcome data from image-guided therapy modification. We review here our experiences with two hypoxia-avid agents [(18)F]fluoroerythronitromidazole (FETNIM) and [(18)F] 2-(2-nitro-1-H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)-acetamide (EF5) and focus on the similarities and differences of these two tracers in comparison to other radiolabeled 2-nitroimidazoles. It is recognized that only [(18)F]FMISO has thus far shown clinical utility and newer tracers need to be tested against this circumstance.

Oxygen reactions in high-pressure nitrogen gas studied with optical emission spectroscopy.

A study of some oxygen reactions in irradiated high-pressure (0.34-3.3MPa) nitrogen gas is presented. Nitrogen gas containing < or =1ppm H(2)O and O(2) was irradiated in a closed target chamber with 4.3MeV protons. Optical emission spectra of the NO-gamma (A(2)Sigma(+)-X(2)Pi), the NO-beta (B(2)Pi-X(2)Pi) and the O ((1)S-(1)D) transitions were recorded as a function of irradiation time at four different nitrogen-gas pressures. The results show a coupling between the NO-gamma build-up half time and the NO-beta decay and the O ((1)S-(1)D) decay half times as a function of irradiation time. The binding of free atomic oxygen in reactions forming NO has implications for the balance of [(11)C]CO(2) versus [(11)C]CO production.

2-[(18)F]fluoro-2-deoxy-D-glucose combined with microdialysis can be used for the comparison of tissue glucose metabolism in obese and lean rats.

AIMS: Direct assessment of tissue metabolism in vivo is important to understand the pathogenesis of obesity. Labelled glucose analogues are potential candidates to be used for this purpose. The aim of this study was to compare the kinetics and metabolism of 2-[(18)F]fluoro-2-deoxy-D-glucose (FDG) in obese (fa/fa) and lean (Fa/?) Zucker rat tissues with microdialysis, and the measurement of uptake and phosphorylation with or without insulin bolus injection. METHODS: Obese (n = 10) and lean (n = 11) anaesthetized rats underwent a microdialysis study after FDG-injection either with or without insulin stimulation. Microdialysis probes were inserted in the jugular vein, quadriceps muscle and liver. After 110 min, tissue [(18)F]-uptake and intracellular phosphorylation of FDG were studied in blood, liver, skeletal muscle, subcutaneous adipose tissue, intra-abdominal adipose tissue and hypothalamus. RESULTS: When measured with microdialysis, insulin-enhanced FDG disappeared from the blood pool and interstitial space of skeletal muscle and liver more effectively in lean rather than in obese animals. Insulin-stimulated skeletal muscle and adipose tissue[(18)F]-uptake was impaired in obese Zucker rats compared with lean animals. Hypothalamic FDG uptake was six to sevenfold higher than in other measured tissues, but was attenuated in obese rats. In liver and in mesenteric fat, insulin-enhanced FDG phosphorylation in lean rats compared with obese animals. CONCLUSIONS: Positron-emitting glucose analogue FDG, combined with microdialysis and tissue analysis, is a feasible method in studying glucose metabolism at the cellular level in animal studies.

Imaging of blood flow and hypoxia in head and neck cancer: initial evaluation with [(15)O]H(2)O and [(18)F]fluoroerythronitroimidazole PET.

UNLABELLED: Hypoxia is a characteristic feature of malignant tumors that should be evaluated before the start of therapy. (18)F-labeled fluoroerythronitroimidazole (FETNIM) is a possible candidate for imaging tumor hypoxia with PET. Quantitative analysis of [(18)F]FETNIM uptake in vivo is necessary before proceeding to assays predicting hypoxia. METHODS: Eight patients with untreated head and neck squamous cell carcinoma were enrolled in the study. All patients underwent dynamic PET imaging with [(18)F]FETNIM, coupled with measurements of blood flow with [(15)O]H(2)O and blood volume with [(15)O]CO. The metabolically active tumor volume was determined from [(18)F]FDG PET performed on a separate day. [(18)F]FETNIM uptake in the tumor was correlated with that in neck muscles and arterial plasma and compared with the findings of other PET studies. RESULTS: Blood flow in tumor was 5- to 30-fold greater than in muscle, in contrast to blood volume, which did not significantly differ in the 2 tissues. With [(18)F]FETNIM PET, muscle activity remained invariably less than plasma activity, whereas activity in whole tumors was always greater than that in muscle. In 4 instances, the maximum tumor uptake of [(18)F]FETNIM was 1.2-2.0 times higher than plasma activity in the late dynamic phase. A kinetic model developed for calculation of distribution volume of reversibly trapping tracers was successfully applied in the [(18)F]FETNIM studies. Tumor distribution volume correlated strongly with the standardized uptake value of [(18)F]FETNIM between 60 and 120 min and with blood flow but not with the standardized uptake value of [(18)F]FDG. The relationship between [(18)F]FETNIM uptake and the blood flow of the tumor was less obvious on a pixel-by-pixel level. CONCLUSION: Uptake of [(18)F]FETNIM in head and neck cancer is highly variable and seems to be governed by blood flow at least in the early phase of tissue accumulation. Maximum tumor-to-muscle tracer uptake ratios > 180 min were in the range of 1-4, comparing favorably with those reported previously for [(18)F]fluoromisonidazole. Assessment of the distribution volume of [(18)F]FETNIM after the initial blood-flow phase is feasible for subsequent evaluation of hypoxia-specific retention.

Personality traits and brain dopaminergic function in Parkinson's disease.

A distinctive personality type, characterized by introversion, inflexibility, and low novelty seeking, has been suggested to be associated with Parkinson's disease. To test the hypothesis that Parkinson's disease is associated with a specific dopamine-related personality type, the personality structures of 61 unmedicated Parkinson's disease patients and 45 healthy controls were examined. Additionally, in 47 Parkinson's disease patients, the dopaminergic function in the brain was directly measured with 6-[(18)F]fluoro-l-dopa ((18)F-dopa) positron emission tomography (PET) with MRI coregistration. The novelty-seeking personality score, supposedly associated with the parkinsonian personality, was slightly lower in the Parkinson's disease group compared with controls, but it did not have a significant relationship with (18)F-dopa uptake in any of the brain regions studied (r = -0.12 to 0.11, P > 0.15). The harm-avoidance personality score, associated with anxiety and depression, was clearly increased in patients with Parkinson's disease and it had a paradoxical, highly significant positive correlation with the (18)F-dopa uptake in the right caudate nucleus (r = 0.53, P = 0.04, Bonferroni corrected for 220 comparisons). Although the results of this study are not in disagreement with the concept of low-novelty-seeking personality type in Parkinson's disease, the personality type does not seem to be dopamine dependent. The correlation between the personality trait of harm avoidance and (18)F-dopa may reflect a specific feedback circuitry of neurotransmitters that is associated with negative emotionality in Parkinson's disease.

Synthesis of S-([18F]fluoromethyl)-(+)-McN5652 as a potential PET radioligand for the serotonin transporter.

The present study describes the synthesis of the [18F]fluoromethyl analogue of (+)-McN5652 ([18F]FMe-McN) as a new potential tracer for the serotonin transporter. In vitro binding studies have shown that FMe-McN displays only slightly lower affinity for the serotonin transporter (K(i) = 2.3 +/- 0.1 nM) than (+)-McN5652 (K(i) = 0.72 +/- 0.2 nM). The radiofluorinated tracer [18F]FMe-McN was prepared by reaction of normethyl (+)-McN5652 with the fluoromethylation agent [18F]bromofluoromethane in an overall radiochemical yield of 5 +/- 1% (decay-corrected, related to [18F]fluoride) and with high specific radioactivity (200-2,000 GBq/micromol at the end of synthesis).

Decreased striatal dopamine transporter binding in vivo in chronic schizophrenia.

We have previously reported that average striatal dopamine transporter (DAT) binding in vivo is unaltered in neuroleptic-naive first-episode schizophrenic patients [Laakso et al., Am. J. Psychiatry 157 (2000) 269]. However, as it has been suggested that some of the brain changes in schizophrenia may vary depending on the illness phase, we studied DAT density in eight stable, medicated chronic schizophrenic patients and eight matched controls using positron emission tomography and [18F]CFT, a marker of dopamine nerve terminals. [18F]CFT binding potentials were significantly lower in chronic schizophrenic patients than in controls, both in the caudate and the putamen (-9 to -16%). Together with the finding of unchanged average striatal DAT levels in first-episode patients and relative insensitivity of striatal [18F]CFT binding to endogenous dopamine and neuroleptic drugs, the result is in line with a relative loss of striatal dopaminergic nerve terminals and/or decreased expression of DAT in a subset of chronic schizophrenic patients.

Pharmacokinetics of [18F]FETNIM: a potential marker for PET.

UNLABELLED: 18F-labeled fluoroerythronitroimidazole (FETNIM) has been suggested as a marker of tumor hypoxia for use with PET. Our goal was to evaluate the pharmacokinetic properties of [18F]FETNIM in rats and analyze metabolites in human, dog, and rat plasma and urine. Metabolites in liver and tumor homogenates from tumor-bearing rats, as well as the biodistribution of the tracer, were also studied. METHODS: Radio-thin-layer chromatography and digital autoradiography were used to distinguish metabolites from the parent drug in urine and plasma from 8 patients, 3 dogs, and 18 rats, as well as in liver and tumor homogenates from Sprague-Dawley rats bearing 7,12-dimethylbenzanthracene-induced rat mammary carcinoma. Biodistribution of [18F]FETNIM was also studied in rats at 15, 30, 60, 120, and 240 min after tracer injection. RESULTS: Most of the radioactivity in plasma and urine was the unchanged tracer, whereas rat liver homogenates contained almost only metabolites of [18F]FETNIM. None of the species studied showed binding of tracer to plasma proteins. A large variation-3%-70%-in the radioactivity represented by unchanged [18F]FETNIM was found in rat tumor. A negative correlation was found between the percentage of radioactivity represented by unchanged [18F]FETNIM in tumor tissue and tumor uptake (percentage injected dose per gram of tissue) at later times. The highest radioactivity was seen in urine and kidney; the lowest uptake was in fat, cerebellum, and bone matrix. In contrast to matrix, bone marrow had high uptake of 18F. The tumor-to-blood ratio reached a maximum of 1.80 +/- 0.64 at 2 h. CONCLUSION: We conclude that [18F]FETNIM shows low peripheral metabolism, little defluorination, and possible metabolic trapping in hypoxic tumor tissue. These suggest a potential use for this tracer in PET studies on hypoxia of cancer patients.

Positron emission tomography shows that impaired frontal lobe functioning in Parkinson's disease is related to dopaminergic hypofunction in the caudate nucleus.

We examined the relation between the dopaminergic function and the cognitive performance of patients with Parkinson's disease (PD). The subject sample consisted of ten patients in the early course of PD and with no previous antiparkinsonian medication. The dopaminergic function of the caudate nucleus and the putamen was studied with [(18)F]fluorodopa positron emission tomography, and the cognitive performance with a comprehensive battery of neuropsychological tests including tests sensitive to frontal lobe function. The decreased [(18)F]fluorodopa uptake in the right caudate nucleus was found to be related to slow processing time, measured as the difference between the incongruent and the congruent subtests of the Stroop Test (r=-0.85, P=0.002), a similar trend was seen in the left caudate (r=-0.60, P=0.07). Similar correlation was not detected in the putamen. The present findings provide evidence that the decreased dopaminergic function in the right caudate nucleus is related to the impaired performance in tests sensitive to frontal lobe function in patients at an early stage of PD and with no antiparkinsonian medication.

Rate of progression in Parkinson's disease: a 6-[18F]fluoro-L-dopa PET study.

The aim of this study was to investigate the rate of progression in Parkinson's disease (PD) with 6-[(18)F]fluoro-L-dopa (FDOPA) positron emission tomography (PET). We investigated 21 patients with PD and eight healthy controls. Ten of the patients were de novo at the time of the first PET scan and antiparkinsonian medication was started thereafter, with a favourable response. A FDOPA PET scan was carried out twice at an approximately 5-year interval. The regions of interest were drawn on individual magnetic resonance imaging (MRI) images, matched with the PET images. At the first PET scan, in PD patients the mean k(i)(occ) (x 10(-3) min(-1)) in the anterior putamen was 5.6 +/- 2.7 (mean +/- S.D.; 55% of the control mean) and in the posterior putamen 4.5 +/- 2.4 (45% of the control mean). The k(i)(occ) value for the caudate nucleus was 7.5 +/- 2.1 (x 10(-3) min(-1); 76% of the control mean). The FDOPA uptake declined by the time of the second PET scan and the annual rate of decline was 8.3 +/- 6.3% (P < 0.001) of the baseline mean in the anterior putamen and 10.3 +/- 4.8% (P < 0.001) in the posterior putamen. In the caudate nucleus, FDOPA uptake decreased by 5.9 +/- 5.1% (P < 0.001) of the baseline mean per year. The estimated preclinical period was longest for the posterior putamen being 6.5 years. For the anterior putamen the preclinical period was 4.6 years. In the caudate nucleus, the estimated FDOPA uptake was at normal level at disease onset. In healthy controls, there was no significant decline in FDOPA uptake in any striatal subregion. Our results suggest that the disease process in PD first affects posterior putamen, followed by the anterior putamen and the caudate nucleus, but once started, the absolute rate of decline is the same. In healthy controls, no significant decline in FDOPA was detected.

Increased frontal [(18)F]fluorodopa uptake in early Parkinson's disease: sex differences in the prefrontal cortex.

Previous imaging studies in Parkinson's disease have focused mainly on the striatum, a region with very high dopaminergic activity. Using modern high-sensitivity 3D [(18)F]fluorodopa (Fdopa)-PET, mesocortical monoamine projections can be studied. To study the frontal monoaminergic system in unmedicated early Parkinson's disease in vivo, we examined 20 early Parkinson's disease patients (10 women, 10 men) and 16 healthy subjects (nine women, seven men) with 3D Fdopa-PET, using standard region-of-interest-based analysis with MRI co-registration. Women with Parkinson's disease had 87% higher Fdopa uptake in the right dorsolateral prefrontal cortex (area 46) compared with men with Parkinson's disease, whereas there was no sex difference in the control group (sex x disease interaction, P = 0.03). The uptake in the right dorsolateral prefrontal cortex was 82% higher in men with Parkinson's disease and 219% higher in women with Parkinson's disease compared with control groups (effect of disease, P < 0.0001). Also in the left dorsolateral prefrontal cortex and in the medial frontal cortex, early Parkinson's disease patients had significantly (18-94%) higher Fdopa uptake compared with healthy controls. In the putamen, both men and women with Parkinson's disease had a significantly lower (27-46%) uptake compared with healthy controls. These results indicate that frontal monoaminergic activity is increased and that there is a sex difference in the prefrontal monoaminergic system in early Parkinson's disease. The reported sex difference may be linked to clinical sex differences in the symptoms and treatment response in Parkinson's disease.

[(18)F]FDOPA and [(18)F]CFT are both sensitive PET markers to detect presynaptic dopaminergic hypofunction in early Parkinson's disease.

The aim of this study was to compare two PET ligands, 6-[(18)F]fluoro-L-dopa ([(18)F]FDOPA) and (18)F-labeled CFT, 2beta-carbomethoxy-3beta-(4-[(18)F]-fluorophenyl)tropane ([(18)F]CFT), in detecting presynaptic dopaminergic hypofunction in early Parkinson's disease (PD). These ligands reflect different aspects of presynaptic dopaminergic function, since [(18)F]FDOPA mainly reflects 6-[(18)F]fluorodopamine (fluorodopamine) synthesis and storage whereas [(18)F]CFT uptake is related to dopamine transporter function. Eight de novo patients with PD who had never been on antiparkinsonian medication were investigated with [(18)F]FDOPA and [(18)F]CFT PET. Five healthy volunteers were studied as controls. In PD patients, both [(18)F]FDOPA and [(18)F]CFT uptakes were significantly reduced both in the contralateral and ipsilateral anterior and posterior putamen. The reduction was greatest in the contralateral posterior putamen (to 28% of control mean for [(18)F]FDOPA, P < 0.0001 and to 16% for [(18)F]CFT, P < 0.0001). Individually, all patients' [(18)F]FDOPA and [(18)F]CFT uptake values in the contralateral anterior and posterior putamen were below 3 SD of the control mean. In the caudate nucleus, the mean uptake of both tracers was significantly reduced both ipsilaterally and contralaterally, but less severely than in the putamen (to 69% of the control mean for [(18)F]FDOPA, P = 0.003 and to 60% for [(18)F]CFT, P = 0.001 contralaterally). Our results show that both [(18)F]FDOPA as well as [(18)F]CFT sensitively detect presynaptic dopaminergic hypofunction in early PD. They demonstrate a considerable reduction of tracer uptake that is greatest in the posterior putamen, followed by the anterior putamen and the caudate nucleus.

Automated synthesis and purification of [18F]bromofluoromethane at high specific radioactivity.

[18F]Bromofluoromethane was synthesised from dibromomethane by substitution of bromine with [18F]fluoride. The synthesis and separation of the [18F]bromofluoromethane were automated. [18F]Bromofluoromethane was used to convert a phenolic and a thiophenolic precursor into a labelled ether and thioether, respectively. The specific radioactivity of these labelled products was determined with both high-performance liquid chromatography (with UV-absorbance detection) and liquid chromatography (with mass spectrometric detection). The median for the specific radioactivity, corrected at the end of radionuclide production, was 934GBq/micromol (range 40-9900 GBq/micromol; n = 83).

Detection of response to COMT inhibition in FDOPA PET in advanced Parkinson's disease requires prolonged imaging.

The aim was to investigate whether the improved 6-[(18)F]fluoro-L-dopa (FDOPA) availability induced by catechol-O-methyltransferase (COMT) inhibition can be more clearly seen during late than during standard (early) imaging in FDOPA uptake in Parkinson's disease (PD) patients with severe dopaminergic hypofunction. Six PD patients and six healthy controls were investigated up to 3.5 h after FDOPA injection with and without a single 400-mg dose of a peripheral COMT inhibitor, entacapone. Prolonged (late) imaging showed a significantly higher increase in FDOPA uptake than standard 1.5 h (early) imaging after entacapone both in controls and in PD patients. The increase in the (putamen-occipital):occipital ratios was 37.4% during early and 70.4% during late imaging in controls. In PD patients, there was no significant change in the ratios during early imaging, but the late imaging showed a significant increase in the putamen-to-occipital ratio of 54.2% after COMT inhibition. Late imaging reveals more clearly the prolonged FDOPA availability induced by COMT inhibition leading to higher cumulated striatal activity compared with early imaging. This might be worth considering in FDOPA studies, especially if investigations are planned to do without blood sampling. Late imaging shows the storing potential of FDA better than is seen during early FDOPA PET imaging after entacapone administration. In patients with severe presynaptic dopaminergic hypofunction, its detection requires prolonged imaging.