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Purpose: To determine the value of diffusion-weighted MRI (DWI-MRI) for treatment response assessment in 2-[18F]fluoro-2-deoxy-D-glucose (FDG)–avid lymphoma. Experimental Design: Patients with FDG-avid Hodgkin (HL) or non-Hodgkin lymphoma (NHL) at pretherapeutic 18F-FDG-PET/CT, who had also undergone pretherapeutic whole-body DWI-MRI, were included in this prospective study. Depending on the histologic lymphoma subtype, patients received different systemic treatment regimens, and follow-up DWI-MRI and 18F-FDG-PET/CT were performed at one or more time points, depending on the clinical course. For each follow-up DWI-MRI, region-based rates of agreement, and rates of agreement in terms of treatment response (complete remission, partial remission, stable disease, or progressive disease), relative to the corresponding 18F-FDG-PET/CT, were calculated. Results: Sixty-four patients were included: 10 with HL, 22 with aggressive NHL, and 32 with indolent NHL. The overall region-based agreement of DWI-MRI with 18F-FDG-PET/CT was 99.4%. For the 51 interim examinations (performed after 1–3 therapy cycles), region-based agreement of DWI-MRI with 18F-FDG-PET/CT was 99.2%, and for the 48 end-of-treatment examinations, agreement was 99.8%. No significant differences, in terms of region-based agreement between DWI-MRI and 18F-FDG-PET/CT, were observed between the three lymphoma groups (HL, aggressive NHL, indolent NHL; P = 0.25), or between interim and end-of-treatment examinations (P = 0.21). With regard to treatment response assessment, DWI-MRI agreed with 18F-FDG-PET/CT in 99 of 102 follow-up examinations (97.1%), with a κ value of 0.94 (P < 0.0001). Conclusions: In patients with FDG-avid lymphoma, DWI-MRI may be a feasible alternative to 18F-FDG-PET/CT for follow-up and treatment response assessment. Clin Cancer Res; 21(11); 2506–13. ©2015 AACR.

PURPOSE To determine whether interim F-FDG PET or interim diffusion-weighted magnetic resonance imaging (DWI) can predict the end-of-treatment (EOT) outcome after immunotherapy in patients with FDG-avid extranodal marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT). MATERIALS AND METHODS Patients with untreated MALT lymphoma prospectively underwent whole-body F-FDG PET/CT and DWI before treatment (baseline), and after three cycles (interim) of rituximab-based immunotherapy. Maximum and mean standardized uptake values (SUVmax, SUVmean), and minimum and mean apparent diffusion coefficients (ADCmin, ADCmean), were measured for up to three target lesions per patient. Rates of change between baseline and interim examinations (ΔSUVmax, ΔSUVmean, ΔADCmin, and ΔADCmean) were compared, using ANOVAs, between the four end-of-treatment (EOT, after six cycles of immunotherapy) outcomes: complete remission (CR), partial remission (PR), stable disease (SD), or progressive disease (PD). RESULTS Fifteen patients with 25 lesions were included. Lesion-based post hoc tests showed significant differences between CR and PR for ΔSUVmax (P < 0.001), ΔSUVmean (P < 0.001), and ΔADCmin (P = 0.044), and between CR and SD for ΔSUVmax (P < 0.001), ΔSUVmean (P < 0.001), ΔADCmin (P = 0.021), and ΔADCmean (P = 0.022). No lesion showed PD at EOT. CONCLUSIONS Both quantitative interim F-FDG PET and interim DWI may possibly be useful to predict complete remission at end-of-treatment in MALT lymphoma patients after immunotherapy.

Dysregulation of the hypothalamic-pituitary-adrenocortical axis with deficient glucocorticoid feedback and alterations in the serotonergic system have been identified as biological correlates of mood disorders. Close examination of the interaction between these systems may offer insights into the pathophysiology of anxiety disorders and depression to understand how stress and these disorders are related. In this study, we investigated the relationship between plasma levels of cortisol and the dominant inhibitory serotonergic receptor, serotonin-1A (5-HT1A). Using positron emission tomography (PET) and the radioligand [carbonyl-11C]WAY-100635, we quantified the 5-HT1A receptor binding. Data from 12 male patients with social phobia and 18 matched control subjects were analysed. Seven brain regions were investigated: the anterior and posterior cingulate cortices, hippocampus, amygdala, medial orbitofrontal and retrosplenial cortices, and dorsal raphe nucleus. Partial correlation analysis, controlled for age and radiochemical variables, was performed to demonstrate the association between cortisol plasma levels and 5-HT1A receptor binding. Cortisol plasma levels were significantly lower in patients with social phobia compared to healthy controls. Moreover, we found strong negative correlations between cortisol plasma levels and 5-HT1A binding in the amygdala (r=-0.93, p=0.0004), hippocampus (r=-0.80, p=0.009), and retrosplenial cortex (r=-0.48, p=0.04) in patients with social phobia. Within the former two regions, these associations were significantly higher in patients than in healthy controls. This PET study confirms a negative association between plasma cortisol levels and the 5-HT1A receptor distribution consistent with studies in rodents and non-human primates. Dysregulation of the cortisol level might increase the vulnerability for mood disorders by altering limbic 5-HT1A receptors.

Objective The authors report imaging findings in a series of 16 patients with MCC, a rare tumour which is often managed primarily by a dermatologist. To our knowledge, no equivalent series of MCC has been described in the nuclear medicine literature. Material and Methods In this IRB-approved retrospective noncomparative case series 16 patients with biopsy-proven Merkel cell carcinoma were included between January 1999 and October 2007. Twenty-nine whole body PET scans (18F-FDG n = 24, 18F-FDOPA n = 5) in 16 patients were retrospectively reviewed with regard to tracer uptake in six anatomical sites per patient. For 127/144 of FDG-PET evaluated regions and 68/144 of regions depicted by conventional imaging methods, a valid standard of reference could be obtained. A combined standard of reference was applied, which consisted of histopathology (lymphadenectomy or biopsy) or clinical or radiological follow-up for at least 12 months. Results: the mean FDG uptake over the clinicopatholigical verified FDG avid areas was 4.7 SUV (1.5–9.9 SUV). The region based assessment of diagnostic value, in consideration of the standard of reference, resulted in a sensitivity of 85.7% and a specificity of 96.2% of FDG-PET (n = 127) and in a combined sensitivity of 95.5% and a specificity of 89.1% for morphological imaging methods (n = 68). Differences between methods did not reach statistical significance (p = 1.00, p = 0.18). Conclusions FDG-PET is a highly useful whole body staging method of comparable value compared to conventional imaging methods with restricted field of view. The lessons learned from case series are discussed.

Objectives: Various studies indicate that serotonin regulates impulsivity and the inhibitory control of aggression. Aggression is also known to be modified by sex hormones, which exert influence on serotonergic neurotransmission. The present study aimed to elucidate potential interactions between human aggression, the inhibitory serotonergic 5‐HT(1A) receptor, and sex hormones. Experimental Design: Thirty‐three healthy volunteers (16 women, aged 26.24 ± 5.5 yr) completed a validated questionnaire incorporating five dimensions of aggression. Subsequently, all subjects underwent positron emission tomography with the radioligand [carbonyl‐(11)C]WAY‐100635 to quantify 5‐HT(1A) binding potentials (BP(ND)s) in the prefrontal cortex, limbic areas, and midbrain. Also, plasma levels of testosterone, 17ß‐estradiol and sex hormone‐binding globulin (SHBG) were measured. Relations between aggression scores, regional 5‐HT(1A) BP(ND)s, and hormone levels were analyzed using correlations, multivariate analyses of variance, and linear regressions. Principal Observations: Statistical analyses revealed higher 5‐HT(1A) receptor BP(ND)s in subjects exhibiting higher aggression scores in prefrontal (all P < 0.041) and anterior cingulate cortices (P = 0.016). More aggressive subjects were also characterized by lower SHBG levels (P = 0.015). Moreover, higher SHBG levels were associated with lower 5‐HT(1A) BP(ND)s in frontal (P = 0.048) and cingulate cortices (all P < 0.013) and in the amygdala (P = 0.03). Conclusions: The present study provides first‐time evidence for a specific interrelation between the 5‐HT(1A) receptor distribution, sex hormones, and aggression in humans. Our findings point to a reduced down‐stream control due to higher amounts or activities of frontal 5‐HT(1A) receptors in more aggressive subjects, which is presumably modulated by sex hormones. Hum Brain Mapp 30:2558–2570, 2009. © 2008 Wiley‐Liss, Inc.

Purpose The aim of this study was to assess the influence of age on the functional activity of the multidrug efflux transporter P-glycoprotein (P-gp) at the human blood-brain barrier. Methods Seven young (mean age: 27±4 years) and six elderly (mean age: 69±9 years) healthy volunteers underwent dynamic (R)-[ 11 C]verapamil (VPM) positron emission tomography (PET) scans and arterial blood sampling. Parametric distribution volume (DV) images were generated using Logan linearisation, and age groups were compared with statistical parametric mapping (SPM). Brain regions that SPM analysis had shown to be most affected by age were analysed by a region of interest (ROI)-based approach using a maximum probability brain atlas, before and after partial volume correction (PVC). Results SPM analysis revealed significant clusters of DV increases in cerebellum, temporal and frontal lobe of elderly compared to younger subjects. In the ROI-based analysis, elderly subjects showed significant DV increases in amygdala (+30%), insula (+26%) and cerebellum (+25%) before PVC, and in insula (+33%) after PVC. Conclusions Increased VPM DV values in the brains of elderly subjects suggest a decrease in cerebral P-gp function with increasing age.

Aims Chronic heart failure (CHF) is frequently associated with a decreased haemoglobin level, whereas the mechanism remains largely unknown. Methods and results One hundred consecutive CHF patients without anaemia or renal dysfunction based on non-cardiac reasons were enrolled. We explored determinants of anaemia (as iron parameters, erythropoietin, hepcidin and kidney function) including red cell volume (RCV) (by a 51 Cr assay) as well as related markers and plasma volume. The influence of each factor on haemoglobin concentrations was determined in a multiple regression model. Mean haemoglobin concentrations were 11.7 +/- 0.8 mg/dL in anaemic CHF patients and 14.4 +/- 1.2 mg/dL in non-anaemic patients. Corrected reticulocytes were lower in anaemic patients (35.1 +/- 15.7 vs. 50.3 +/- 19.2 G/L, P = 0.001), but the RCV was not reduced (1659.3 +/- 517.6 vs. 1826.4 +/- 641.3 mL, P = 0.194). We found that plasma volumes were significantly higher in anaemic CHF patients (70.0 +/- 2.4 vs. 65.0 +/- 4.0%, P0.001). Plasma volume was the best predictor of haemoglobin concentrations in the regression model applied (B = -0.651, P0.001, R(2) = 0.769). Conclusion Haemodilution appears to be the most potent factor for the development of low haemoglobin levels in patients with CHF. Our data support an additional independent, but minor influence of iron deficiency on haemoglobin concentrations in CHF patients.

The higher prevalence rates of depression and anxiety disorders in women compared to men have been associated with sexual dimorphisms in the serotonergic system. The present positron emission tomography (PET) study investigated the influence of sex on the major inhibitory serotonergic receptor subtype, the serotonin-1A (5-HT(1A)) receptor.Sixteen healthy women and 16 healthy men were measured using PET and the highly specific radioligand [carbonyl-(11)C]WAY-100635. Effects of age or gonadal hormones were excluded by restricting the inclusion criteria to young adults and by controlling for menstrual cycle phase. The 5-HT(1A) receptor BP(ND) was quantified using (1) the 'gold standard' manual delineation approach with ten regions of interest (ROIs) and (2) a newly developed delineation method using a PET template normalized to the Montreal Neurologic Institute space with 45 ROIs based on automated anatomical labeling.The 5-HT(1A) receptor BP(ND) was found equally distributed in men and women applying both the manual delineation method and the automated delineation approach. Women had lower mean BP(ND) values in every region investigated, with a borderline significant sex difference in the hypothalamus (p = 0.012, uncorrected). There was a high intersubject variability of the 5-HT(1A) receptor BP(ND) within both sexes compared to the small mean differences between men and women.To conclude, when measured in the follicular phase, women do not differ from men in the 5-HT(1A) receptor binding. To explain the higher prevalence of affective disorders in women, further studies are needed to evaluate the relationship between hormonal status and the 5-HT(1A) receptor expression.

Receptor distribution patterns of neurotransmitters and distinct functional fields of the human brain appear to be tightly connected with respect to their topological allocation along the cerebral cortex. There is, however, considerable lack of human data directly demonstrating this association in vivo. Here, we assessed the relationship between the distribution of the major inhibitory serotonergic neurotransmitter receptor, the 5-HT(1A) subtype, and the functional organization within early visual cortex defined by retinotopic mapping. The 5-HT(1A) receptor-binding potential was quantified by positron emission tomography (PET) using the highly selective and specific radioligand [carbonyl-(11)C]WAY-100635 in seven healthy subjects. The retinotopic maps and borders determined by functional magnetic resonance imaging (fMRI) were compared to the receptor distribution employing surface-based region of interest analysis in each of these subjects. We found a significant difference in receptor-binding potential in the functionally defined primary (V1) compared to secondary (V2) visual area, as V1 exhibits only 68% of receptor binding found in V2 in both hemispheres, which is consistent with postmortem data. Our in vivo findings clearly support prior assumptions of a link between receptor distribution and functional fields of the human cortex.

Introduction Changes of the adenosine A 3 receptor subtype (A3AR) expression have been shown in a variety of pathologies, especially neurological and affective disorders, cardiac diseases and oncological and inflammation processes. Recently, 5-(2-fluoroethyl) 2,4-diethyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate (FE@SUPPY) was presented as a high-affinity ligand for the A3AR with good selectivity. Our aims were the development of a suitable labeling precursor, the establishment of a reliable radiosynthesis for the fluorine-18-labeled analogue [ 18 F]FE@SUPPY and a first evaluation of [ 18 F]FE@SUPPY in rats. Methods [ 18 F]FE@SUPPY was prepared in a feasible and reliable manner by radiofluorination of the corresponding tosylated precursor. Biodistribution was carried out in rats, and organs were removed and counted. Autoradiography was performed on rat brain slices in the presence or absence of 2-Cl-IB-MECA. Results Overall yields and radiochemical purity were sufficient for further preclinical and clinical applications. The uptake pattern of [ 18 F]FE@SUPPY found in rats mainly followed the described mRNA distribution pattern of the A3AR. Specific uptake in brain was demonstrated by blocking with a selective A3AR agonist. Conclusion We conclude that [ 18 F]FE@SUPPY has the potential to serve as the first positron emission tomography tracer for the A3AR.

AIMS Nuclear imaging may have an increasing role in the diagnosis of hepatocellular carcinoma (HCC). The aim of this study was to compare prospectively the Gallium-67 citrate ((67)Ga) scintigraphy results with those obtained by positron emission tomography (PET) using (11)C-acetate in patients with HCC. METHODS We prospectively analysed 21 patients (mean age, 64+/-11 years) with histopathologically verified HCC undergoing (11)C-acetate PET and (67)Ga scintigraphy. (67)Ga scans were not performed in three of these 21 patients due to the exacerbation of the disease. Whole-body (11)C-acetate PET were performed following intravenous injection of 850 MBq of (11)C-acetate. For (67)Ga scintigraphy, whole-body, planar and single photon emission computed tomography imaging acquisitions were performed after intravenous application of a mean dose of 189 MBq (67)Ga. RESULTS (67)Ga scintigraphy found abnormalities only in 10 of 18 patients (56%) and detected 22 of 46 clinically involved sites (48%); it was false-positive in two patients. (11)C-acetate PET found abnormalities in 14 of 18 patients (78%) and detected 36 of 46 clinical lesions (78%); it was false-positive in one patients. In one patient with left supraclavicular lymph node metastases, neither the (67)Ga scintigraphy nor the conventional computed tomography have shown the lesions, which were clearly demonstrated by the (11)C-acetate PET. CONCLUSION Our results indicate significantly higher sensitivity and specificity of (11)C-acetate PET than (67)Ga scan in detection of HCC lesions. This study suggests that imaging with (11)C-acetate PET might play a potential role in the diagnostic workup of patients with HCC.

Functional imaging of the adrenal cortex by means of PET may play an important clinical role. Recently, we presented the synthesis and first evaluation of a novel 11beta-hydroxylase inhibitor, [(18)F]FETO, in rats displaying high tracer accumulation in the adrenals. In this study, we aimed to investigate for the first time the potency of [(18)F]FETO as a PET tracer for the adrenal cortex in humans.An average preparation yielded 1-2 GBq of [(18)F]FETO ready to use. Ten healthy volunteers aged 24-57 years (five male and five female) were included in the study. After i.v. administration of 365 MBq [(18)F]FETO (246-391 MBq), dynamic images were acquired in 2D standard mode in 14 frames over 45 min. Afterwards, whole-body scanning was performed. In addition to visual interpretation, semi-quantitative analysis using standardised uptake values (SUVs) was conducted.[(18)F]FETO distribution was similar in all scanned volunteers. Visually, pronounced accumulation of [(18)F]FETO was found in the adrenals, whereas moderate uptake was observed-at least in some of the subjects-for liver, renal calices, gallbladder, stomach walls and pancreas. Kidney and bowels showed only faint uptake. Median SUVs for the right and left adrenal glands were 15.6 (10.0-28.6) and 15.7 (10.3-35.9), respectively. The reference tissue (liver) displayed a median SUV of 2.5 (2.2-4.6).[(18)F]FETO is a valuable tracer for adrenocortical PET imaging, combining the longer half-life of( 18)F with a high 11beta-hydroxylase selectivity. In accordance with our findings in rats, FETO PET revealed very high accumulation in the adrenal glands in healthy volunteers.

SummaryMetabolic imaging with 2-[fluorine-18]-fluoro- 2-deoxy-D-glucose (FDG) is actually considered as the best method to detect and quantitatively assess myocardial tissue viability. The aim of this study was to investigate the accuracy of FDG gamma camera positron emission tomography (GCPET) imaging equipped with one inch NaI crystals in comparison to FDG dedicated PET (dPET) imaging as a „gold standard“ in phantom and clinical studies. Patients, methods: Nineteen patients with coronary artery disease (CAD) underwent both imaging modalities. Phantom and clinical GCPET imaging were performed with a dual-headed, coincidence based gamma camera equipped with 1 inch thick NaI crystals and an x-ray tube (XCT) for attenuation correction (AC), as well as with a dedicated PET scanner with AC. 99mTc tetrofosmin single-photon emission tomography (SPET) studies were performed for assessment of myocardial perfusion, with AC. Results: Phantom studies showed a significant relation in segmental activity between FDG imaging with AC using GCPET and dPET (r = 0.91, p

Summary Background : Local treatment with foams in patients suffering from ulcerative proctitis or proctosigmoiditis is considered a rational treatment option. Aims : To investigate colonic spread, safety, tolerability and acceptance of a newly developed budesonide foam formulation. Methods : Twelve patients (four females, eight males) with acute proctosigmoiditis or left-sided ulcerative colitis were rectally administered a single dose of [99Tcm]-labelled budesonide foam (Budenofalk; Dr Falk Pharma GmbH, Freiburg, Germany) containing 2 mg budesonide in 20 mL foam after diagnostic colonoscopy. Thereafter, the colonic spread was assessed by means of γ-scintigraphy for 6 h. Serum samples were taken simultaneously. Results : Budesonide foam spread with a maximum between 11 and 40 cm, thus reaching the sigmoid colon in all patients. In some patients, the foam even extended into the distal third and the middle of the descending colon with maximum radioactivity at 4 h. Systemic budesonide absorption was rapid and pharmacokinetic data were comparable with published data on marketed budesonide enemas, with mean serum Cmax and AUC0-8h values of 0.8 ± 0.5 ng/mL and 3.7 ± 1.9 ng h/mL, respectively. The new formulation was well accepted by all patients, who could retain the foam for at least 4 h. Conclusions : In the majority of patients, budesonide foam effectively spread up to the left-sided colon and thus qualifies for the local treatment of proctosigmoiditis.

In advanced seminoma the management of residuals after completion of chemotherapy is controversial. Some centres routinely perform surgery for lesionsor =3 cm diameter, others recommend surgery solely if the residual fail to shrink or show even growth. This study prospectively investigates whether FDG PET can improve the prediction of viable tumour in post-chemotherapy seminoma residuals.After an expansion of a previous study population, 54 patients from eight centres with metastatic seminoma and a CT-documented mass after chemotherapy were included in the study. Six patients were excluded from evaluation because of protocol violations. After PET, the patients underwent either surgery or were followed clinically. On follow-up the lesions were considered to be non-viable when there was unequivocal shrinking, or when the lesion remained morphologically stable for at least 24 months. Any lesion growth was assumed to be malignant. PET results were compared to CT discrimination (oror =3 cm) of the residual masses.Fifty-two PET scans were evaluable. After adequate chemotherapy, there were 74 CT-documented residual masses ranging in size from 1 to 11 cm (median, 2.2 cm). Their dignities were confirmed histologically in 13 lesions, or by follow-up CT in 61 lesions. Four of forty-seven lesions3 cm and 11/27 lesionsor =3 cm were viable. PET was true positive in one lesion3 cm and in 11 lesionsor =3 cm, false negative in three lesions3 cm, and true negative in 59 lesions (43 lesions3 cm). No PET scan was false positive. In detecting viability the sensitivity and specificity was 73% (95% CI, 44-88), and 73% (59-83), respectively, for CT (oror =3 cm); and 80% (51-95), and 100% (93-100), respectively, for PET (specificity, P0.001).In post-chemotherapy seminoma residuals, a positive PET is highly predictive for the presence of viable tumour. The specificity of PET is significantly higher than that of CT when using aor =3 cm cut-off. A negative PET scan is excellent for the exclusion of disease in lesionsor =3 cm, with a somewhat higher sensitivity than CT (n.s.). PET can contribute to the management of residual seminoma lesions, especially in terms of avoiding unnecessary additional treatment for patients with lesionsor =3 cm.

The biodistribution and pharmacokinetics of the fluorine-18-labeled fluoroquinolone antibiotic [ 18 F]ciprofloxacin in tissue were studied noninvasively in humans by means of positron emission tomography (PET). Special attention was paid to characterizing the distribution of [ 18 F]ciprofloxacin to select target tissues. Healthy volunteers ( n = 12) were orally pretreated for 5 days with therapeutic doses of unlabeled ciprofloxacin. On day 6, subjects received a tracer dose (mean injected amount, 700 ± 55 MBq, which contained about 0.6 mg of unlabeled ciprofloxacin) of [ 18 F]ciprofloxacin as an intravenous bolus. Thereafter, PET imaging and venous blood sampling were initiated. Time-radioactivity curves were measured for liver, kidney, lung, heart, spleen, skeletal muscle, and brain tissues for up to 6 h after radiotracer administration. The first application of [ 18 F]ciprofloxacin in humans has demonstrated the safety and utility of the newly developed radiotracer for pharmacokinetic PET imaging of the tissue ciprofloxacin distribution. Two different tissue compartments of radiotracer distribution could be identified. The first compartment including the kidney, heart, and spleen, from which the radiotracer was washed out relatively quickly (half-lives [ t 1/2 s], 68, 57, and 106 min, respectively). The second compartment comprised liver, muscle, and lung tissue, which displayed prolonged radiotracer retention ( t 1/2 , >130 min). The highest concentrations of radioactivity were measured in the liver and kidney, the main organs of excretion (standardized uptake values [SUVs], 4.9 ± 1.0 and 9.9 ± 4.4, respectively). The brain radioactivity concentrations were very low (−1 ) and could therefore not be quantified. Transformation of SUVs into absolute concentrations (in micrograms per milliliter) allowed us to relate the concentrations at the target site to the susceptibilities of bacterial pathogens. In this way, the frequent use of ciprofloxacin for the treatment of a variety of infections could be corroborated.

The suitability of the 18F-labelled fluoroquinolone antibiotic ciprofloxacin ([18F]ciprofloxacin) for imaging of bacterial infections with positron emission tomography (PET) was assessed in vitro and in vivo.For the in vitro experiments, suspensions of various E. coli strains were incubated with different concentrations of [18F]ciprofloxacin (0.01-5.0 microg/ml) and radioactivity retention was measured in a gamma counter. For the in vivo experiments, 725 +/- 9 MBq [18F]ciprofloxacin was injected intravenously into four patients with microbiologically proven bacterial soft tissue infections of the lower extremities and time-radioactivity curves were recorded in infected and uninfected tissue for 5 h after tracer injection.Binding of [18F]ciprofloxacin to bacterial cells was rapid, non-saturable and readily reversible. Moreover, bacterial binding of the agent was similar in ciprofloxacin-resistant and ciprofloxacin-susceptible clinical isolates. These findings suggest that non-specific binding rather than specific binding to bacterial type II topoisomerase enzymes is the predominant mechanism of bacterial retention of the radiotracer. PET studies in the four patients with microbiologically proven bacterial soft tissue infections demonstrated locally increased radioactivity uptake in infected tissue, with peak ratios between infected and uninfected tissue ranging from 1.8 to 5.5. Radioactivity was not retained in infected tissue and appeared to wash out with a similar elimination half-life as in uninfected tissue, suggesting that the kinetics of [18F]ciprofloxacin in infected tissue are governed by increased blood flow and vascular permeability due to local infection rather than by a binding process.Taken together, our results indicate that [18F]ciprofloxacin is not suited as a bacteria-specific infection imaging agent for PET.

[(11)C]Flumazenil, a highly selective benzodiazepine antagonist is the most extensively used GABA(A) ligand for PET so far. To overcome half life disadvantages of (11)C a [(18)F]-labeled flumazenil derivative, 2'-[(18)F]fluoroflumazenil (FFMZ) was developed and biologically evaluated with respect to the GABA(A) receptor. Organ with the highest uptake was the pituitary gland. Brain uptake was high and followed the order cortex>thalamus>cerebellum>rest brain. Fluoroflumazenil displaced [(3)H]flumazenil binding from membrane GABA(A) receptors with an IC(50)value (3.5 nM) comparable to that of Flumazenil (2.8 nM). The presented data confirm the potential of [(18)F]FFMZ for PET imaging of the GABA-ergic system.

In the last decade radiolabeled tropane analogs based on β-CIT have proven indispensable for the imaging of the dopamine transporter. However, further improvements in their pharmacodynamic and pharmacokinetic features are desirable. An important improvement, yielding in higher affinity to the dopamine transporter (DAT) vs. serotonin transporter (SERT), can be achieved by a simple replacement of the carboxylic methyl ester group in β-CIT by a fluoroethyl ester. The preparation and ex vivo evaluation of this new β-CIT-analog ([18F]FE@CIT) is presented here. Precursor and standard were prepared from β-CIT and analyzed by spectroscopic methods. Yields of precursor and standard preparation were 61% and 42%, respectively. [18F]FE@CIT was prepared by distillation of [18F]bromofluoroethane ([18F]BFE) and reaction with (1R-2-exo-3-exo)8-methyl-3-(4-iodo-phenyl)-8-azabicyclo[3.2.1] octane-2-carboxylic acid. After 10 min at 150°C the product was purified using a C-18 SepPak. The radiosynthesis evinced radiochemical yields of >90% (based on [18F]BFE), the specific radioactivity was >416 GBq/μmol. An average 30 μAh cyclotron irradiation yielded more than 2.5 GBq [18F]FE@CIT. For the ex vivo bioevaluation, 20 male Sprague-Dawley rats were sacrificed at 5, 15, 30, 60, and 120 min after injection. Organs were removed, weighed, and counted. For autoradiographic experiments, transverse brain slices of about 100 μm were prepared. The ex vivo evaluation showed highest brain uptake in striatal regions, followed by thalamus and cerebellum. The highest striatum to cerebellum ratio was 3.73 and the highest thalamus to cerebellum ratio was 1.65. Autoradiographic images showed a good and differentiated uptake in striatal regions with a good target-to-background ratio. Synapse 55:73–79, 2005. © 2004 Wiley-Liss, Inc.

Angiotensin converting enzyme (ACE) inhibitors as well as angiotensin II receptor antagonists are able to prevent the vasoconstrictive effect of angiotensin II on the efferent renal vessels, which is believed to play an important role in renovascular hypertension. This effect is assumed to be essential for the demonstration of renovascular hypertension by captopril renography. In this study, renographic changes induced by captopril and the AT1 receptor antagonist valsartan were compared in patients with a high probability for renovascular hypertension. Twenty-five patients with 33 stenosed renal arteries (grade of stenosis >50%) and hypertension were studied. Captopril, valsartan and baseline renography were performed within 48 h using technetium-99m mercaptoacetyltriglycine. Blood pressure was monitored, plasma renin concentration before and after intervention was determined and urinary flow was estimated from the urinary output of the hydrated patients. Alterations in renographic curves after intervention were evaluated according to the Santa Fe consensus on ACE inhibitor renography. Captopril renography was positive, indicating renovascular hypertension, in 25 of the 33 stenosed vessels, whereas valsartan renography was positive in only ten. Blood pressure during captopril and valsartan renography was not different; reduction in blood pressure was the same after valsartan and captopril. Plasma renin concentration was comparable for valsartan and captopril studies, showing suppressed values after intervention in as many as 12 of the 25 patients. Urinary flow after valsartan was higher than after captopril (P

1. In a mass balance study, six healthy male volunteers received a single oral dose of 4 mg (14)C-labelled emedastine difumarate. The pharmacokinetics of the total radioactivity and unchanged drug were assessed over 48 h. Urinary and faecal excretion were measured over 120 h. Additionally, urinary metabolites were investigated. 2. In a single- and multiple-dose pharmacokinetic study, nine male and nine female healthy volunteers received 2 mg oral emedastine difumarate b.i.d. or 4 mg o.d. for 7 consecutive days. The plasma pharmacokinetics were assessed on day 1 and at steady-state. 3. The mass balance study demonstrated almost complete gastrointestinal absorption of the administered dose. A total of 94.2% of the radioactivity was eliminated via the kidneys. Unchanged emedastine in the urine accounted for5% of dose. 5-Hydroxy, 6-hydroxy and N-oxide metabolites previously identified in the Japanese were present in Caucasian subjects. 4. AUC after single and multiple dosing were dose-proportional. On day 7, no statistical difference in AUC(0-24) could be detected between the two regimens, with AUC = 70.6 +/- 36.1 and 71.7 +/- 52.3 ng h ml(-1), respectively. There were no gender differences in the pharmacokinetics of emedastine. 5. The results corroborate the use of emedastine in a Caucasian population and support the extrapolation of safety and efficacy data from Asians to Caucasians.

Purpose: To determine the value of diffusion-weighted MRI (DWI-MRI) for pretherapeutic imaging of fluorodeoxyglucose (FDG)-avid lymphoma and lymphoma with variable FDG avidity. Experimental Design: Treatment-naïve patients with lymphoma who were referred for whole-body staging were included in this prospective study. Group A included patients with FDG-avid lymphoma (e.g., Hodgkin, diffuse large B-cell, and follicular lymphoma), whereas Group B included patients with lymphoma of variable FDG avidity [e.g., extranodal marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT)]. All patients underwent DWI-MRI and 18F-FDG- positron emission tomography/computed tomography (PET/CT). Region-based sensitivity and agreement with Ann Arbor staging, relative to the reference standard, were calculated for DWI-MRI, and, in Group B, also 18F-FDG-PET/CT and contrast-enhanced (CE-) CT. Results: In Group A (100 patients), DWI-MRI had a region-based sensitivity of 97%, and with regard to staging, agreed with the reference standard in 94 of 100 patients (κ, 0.92). In Group B (40 patients; 38 MALT lymphomas and 2 small lymphocytic lymphomas/chronic lymphocytic leukemias), DWI-MRI, 18F-FDG-PET/CT, and CE-CT had region-based sensitivities of 94.4%, 60.9%, and 70.7%, respectively. With regard to staging in Group B, DWI-MRI, 18F-FDG-PET/CT, and CE-CT agreed with the reference standard in 37 of 40, 26 of 40, and 24 of 40 patients, with κ values of 0.89, 0.52, and 0.43, respectively. Conclusions: In patients with FDG-avid lymphoma, DWI-MRI seems to be only slightly inferior to 18F-FDG-PET/CT with regard to pretherapeutic regional assessment and staging. In patients with lymphoma subtypes that show a variable FDG avidity (e.g., MALT lymphoma), DWI-MRI seems to be superior to both 18F-FDG-PET/CT and CE-CT. Clin Cancer Res; 20(11); 2984–93. ©2014 AACR.

Adrenal cortical carcinoma (ACC) is a rare malignant neoplasm with a poor prognosis. Radical surgery of the primary tumor and of local as well as of distant recurrence is the only effective treatment, and requires accurate and early localization of recurrent tumors. In this regard, we prospectively scanned 10 patients with ACC, 8 during follow-up and 2 at primary work-up. In all patients PET scans from the neck to the upper thighs were obtained 45 minutes after injection of 370 MBq [18F]FDG. Reading was done visually, with the investigator blinded to the results of other diagnostic modalities. All known sites of ACC lesions showed markedly increased FDG uptake. In 3 patients, previously unknown lesions were identified by PET in the lung (one lesion), the abdomen (3 lesions), and the skeleton (multiple), respectively. One false positive liver focus was shown by PET aside from the true positive lung metastases in the same patient. The sensitivity/specificity of PET based on different organs was 100/97%, that based on the number of PET-detected lesions (N = 23) was 100/95%. PET altered or influenced the tumor stage in 3/10 patients, modifying the subsequent therapeutic management in 2/10 patients. We conclude that FDG-PET is highly useful in ACC and should be included in the work-up for initial staging as well as for follow-up.

OBJECTIVE. Systemic mastocytosis is a hematologic neoplasm characterized by abnormal accumulation and growth of mast cells in one or more organ systems. We analyzed five patients with systemic mastocytosis referred for FDG positron emission tomography who had biopsy-proven mast cell infiltrates in various organs.CONCLUSION. Our findings indicate that FDG positron emission tomography is not useful for staging and follow-up of aggressive systemic mastocytosis.

Climate, in particular sunshine, influences mood and energy levels, creating a positive upswing of mood on bright, sunny days and negative downswing in cold, dark winter seasons. Higher serotonin transporter availability in healthy human subjects in times of lesser light exposure and lower serotonin levels have been shown in winter.We examined the light-dependent variations in serotonin-1A receptor binding in limbic regions in 36 drug-naive healthy human subjects. Receptor binding was quantified using positron emission tomography and the radioligand [carbonyl-¹¹C]WAY-100635. Binding potential values were related to the amount of individual exposure to sunlight (daily duration of sunshine) and global radiation (total light intensity).We found a 20-30% lower serotonin-1A receptor binding in the group exposed to a lower amount of global light radiation. Partial correlation analysis revealed significant positive correlations between the regional postsynaptic serotonin-1A receptor binding and global radiation accumulated over a period of 5 days.Seasonal factors, such as daily amount of sunshine and global radiation, influence serotonin-1A receptor binding in limbic brain regions of healthy human subjects. Combined with recently demonstrated seasonal fluctuations in the serotonin transporter availability, our results underline the importance of seasonal factors in the regulation of the serotonergic transmission.

Propionyl-L-carnitine is a naturally occurring analogue of L-carnitine (LC) produced in the body. PLC administration has shown beneficial effects in cardiovascular pathologies. In ulcerative colitis (UC), oral PLC treatment increased clinical presentation and positively influenced colon histology. In the present study, the MMX Multi Matrix System® (MMX™) was used as drug delivery strategy for targeted PLC colon delivery. A pharmacoscintigraphic study (n = 6 healthy volunteers) described release characteristics of two MMX-PLC-HCl controlled release 500 mg tablets. A pharmacokinetic (PK) parallel group study (n = 24) determined safety, plasma PLC concentrations and PK parameters after single and multiple doses. Gastrointestinal transit was slow and variable. The colon was the main site of PLC release and absorption. After single 500 or 1000 mg PLC doses plasma PLC and LC increased up to 2.6 and 1.2-1.3-fold compared to baseline. Multiple doses of 500 and 1000 mg twice a day over 7 days did not significantly increase maximum plasma concentrations of PLC or LC with respect to concentrations achieved after single dose administration. The colon is the main site of PLC release and absorption from MMX-PLC tablets. A daily dose of 500 mg to 1000 mg PLC twice a day was well tolerated, justifying further studies in patients with pathologies of the distal gastrointestinal tract to evaluate the efficacy of the MMX-PLC formulation.

In microdose studies, the pharmacokinetic profile of a drug in blood after administration of a dose up to 100 μg is measured with sensitive analytical techniques, such as accelerator mass spectrometry (AMS). As most drugs exert their effect in tissue rather than blood, methodology is needed for extending pharmacokinetic analysis to different tissue compartments. In the present study, we combined, for the first time, AMS analysis with positron emission tomography (PET) in order to determine the pharmacokinetic profile of the model drug verapamil in plasma and brain of humans. In order to assess pharmacokinetic dose linearity of verapamil, data were acquired and compared after administration of an intravenous microdose and after an intravenous microdose administered concomitantly with an oral therapeutic dose.Six healthy male subjects received an intravenous microdose [0.05 mg] (period 1) and an intravenous microdose administered concomitantly with an oral therapeutic dose [80 mg] of verapamil (period 2) in a randomized, crossover, two-period study design. The intravenous dose was a mixture of (R/S)-[14C]verapamil and (R)-[11C]verapamil and the oral dose was unlabelled racaemic verapamil. Brain distribution of radioactivity was measured with PET whereas plasma pharmacokinetics of (R)- and (S)-verapamil were determined with AMS. PET data were analysed by pharmacokinetic modelling to estimate the rate constants for transfer (k) of radioactivity across the blood-brain barrier.Most pharmacokinetic parameters of (R)- and (S)-verapamil as well as parameters describing exchange of radioactivity between plasma and brain (influx rate constant [K(1)] = 0.030 ± 0.003 and 0.031 ± 0.005 mL/mL/min and efflux rate constant [k(2)] = 0.099 ± 0.006 and 0.095 ± 0.008 min-1 for period 1 and 2, respectively) were not statistically different between the two periods although there was a trend for nonlinear pharmacokinetics for the (R)-enantiomer. On the other hand, all pharmacokinetic parameters (except for the terminal elimination half-life [t1/2;)]) differed significantly between the (R)- and (S)-enantiomers for both periods. The maximum plasma concentration (C(max)), area under the plasma concentration-time curve (AUC) from 0 to 24 hours (AUC(24)) and AUC from time zero to infinity (AUC(∞)) were higher and the total clearance (CL), volume of distribution (V(d)) and volume of distribution at steady state (V(ss)) were lower for the (R)- than for the (S)-enantiomer.Combining AMS and PET microdosing allows long-term pharmacokinetic data along with information on drug tissue distribution to be acquired in the same subjects thus making it a promising approach to maximize data output from a single clinical study.

Background: Progesterone (P) is thought to influence mood and affective states. Alterations of the inhibitory serotonin-1A (5-HT1A) receptor distribution are associated with depression and anxiety. This study evaluates the influence of plasma P levels on the 5-HT1A receptor binding in healthy male subjects. Methods: Molecular neuroimaging of the 5-HT1A receptor distribution using positron emission tomography and hormone assays for total plasma P and cortisol were done in a sample of 18 healthy men. Results: Plasma P levels explained up to 65% of the variability in 5-HT1A receptor binding in limbic regions including the amygdala, orbitofrontal cortex and retrosplenial cortex. When controlling for cortisol in the model, there was an expected decline in explained variances of 5-HT1A binding attributed to P. Conclusions: The results of this study provide further support for the effect of P on 5-HT1A receptor expression and raise the possibility that P mediates the vulnerability to mood disorders by affecting the serotonergic system.

We performed positron emission tomography using [carbonyl-(11)C]WAY-100635, a serotonin 1A (5-HT(1A)) receptor antagonist, in 13 patients with temporal lobe epilepsy (TLE) and in 13 controls. 5-HT(1A) receptor distribution mapping allowed correct lateralization of the epileptogenic temporal lobe in all patients. 5-HT(1A) receptor binding potential (BP(ND)) was significantly reduced in almost all temporal regions of the epileptogenic lobe. Compared with controls, the patients had significantly decreased BP(ND) values in the hippocampus, parahippocampal gyrus, and amygdala. The asymmetry index (AI), which characterizes the interhemispheric asymmetry in BP(ND), was significantly higher in patients than in controls in most regions. Depression scores were not significantly correlated with BP(ND) or AI values. Our data provide further evidence of functional changes in the serotonergic system in TLE. Molecular imaging of the 5-HT(1A) receptor may help to define the in vivo neurochemistry of TLE, and may provide a valuable tool in the noninvasive presurgical assessment of patients with medically refractory TLE.

We attempted to assess regional differences in cerebral P-glycoprotein (P-gp) function by performing paired positron emission tomography (PET) scans with the P-gp substrate ( R)-[11C]verapamil in five healthy subjects before and after i.v. infusion of tariquidar (2 mg/kg). Comparison of tariquidar-induced changes in distribution volumes ( DVs) in 42 brain regions of interest (ROIs) failed to detect significant differences among brain ROIs. Statistical parametric mapping analysis of parametric DV images visualized symmetrical bilateral clusters with moderately higher DV increases in response to tariquidar administration in cerebellum, parahippocampal gyrus, olfactory gyrus, and middle temporal lobe and cortex, which might reflect moderately decreased P-gp function and expression.

Introduction Recently, [ 18 F]FE@SUPPY and [ 18 F]FE@SUPPY:2 were introduced as the first positron emission tomography (PET) tracers for the adenosine A 3 receptor. Thus, aim of the present study was the metabolic characterization of the two adenosine A 3 receptor PET tracers. Methods In vitro carboxylesterase (CES) experiments were conducted using incubation mixtures containing different concentrations of the two substrates, porcine CES and phosphate-buffered saline. Enzymatic reactions were stopped by adding acetonitrile/methanol (10:1) after various time points and analyzed by a high-performance liquid chromatography (HPLC) standard protocol. In vivo experiments were conducted in male wild-type rats; tracers were injected through a tail vein. Rats were sacrificed after various time points ( n =3), and blood and brain samples were collected. Sample cleanup was performed by an HPLC standard protocol. Results The rate of enzymatic hydrolysis by CES demonstrated Michaelis–Menten constants in a micromolar range (FE@SUPPY, 20.15 μM, and FE@SUPPY:2, 13.11 μM) and limiting velocities of 0.035 and 0.015 μM/min for FE@SUPPY and FE@SUPPY:2, respectively. Degree of metabolism in blood showed the following: 15 min pi 47.7% of [ 18 F]FE@SUPPY was intact compared to 33.1% of [ 18 F]FE@SUPPY:2; 30 min pi 30.3% intact [ 18 F]FE@SUPPY was found compared to 15.6% [ 18 F]FE@SUPPY:2. In brain, [ 18 F]FE@SUPPY:2 formed an early hydrophilic metabolite, whereas metabolism of [ 18 F]FE@SUPPY was not observed before 30 min pi Conclusion Knowing that metabolism in rats is several times faster than in human, we conclude that [ 18 F]FE@SUPPY should be stable for the typical time span of a clinical investigation. As a consequence, from a metabolic point of view, one would tend to decide in favor of [ 18 F]FE@SUPPY.

Tariquidar, a potent, nontoxic, third-generation P-glycoprotein (P-gp) inhibitor, is a possible reversal agent for central nervous system drug resistance. In animal studies, tariquidar has been shown to increase the delivery of P-gp substrates into the brain by severalfold. The aim of this study was to measure P-gp function at the human blood-brain barrier (BBB) after tariquidar administration using PET and the model P-gp substrate (R)-(11)C-verapamil. METHODS: Five healthy volunteers underwent paired (R)-(11)C-verapamil PET scans and arterial blood sampling before and at 2 h 50 min after intravenous administration of tariquidar (2 mg/kg of body weight). The inhibition of P-gp on CD56-positive peripheral lymphocytes of each volunteer was determined by means of the (123)Rh efflux assay. Tariquidar concentrations in venous plasma were quantified using liquid chromatography/mass spectrometry. RESULTS: Tariquidar administration resulted in significant increases (Wilcoxon test for paired samples) in the distribution volume (DV, +24% +/- 15%) and influx rate constant (K(1), +49% +/- 36%) of (R)-(11)C-verapamil across the BBB (DV, 0.65 +/- 0.13 and 0.80 +/- 0.07, P = 0.043; K(1), 0.034 +/- 0.009 and 0.049 +/- 0.009, P = 0.043, before and after tariquidar administration, respectively). A strong correlation was observed between the change in brain DV after administration of tariquidar and tariquidar exposure in plasma (r = 0.90, P = 0.037). The mean plasma concentration of tariquidar achieved during the second PET scan (490 +/- 166 ng/mL) corresponded to 100% inhibition of P-gp function in peripheral lymphocytes. CONCLUSION: Tariquidar significantly increased brain penetration of (R)-(11)C-verapamil-derived activity due to increased influx. As opposed to peripheral P-gp function, central P-gp inhibition appeared to be far from complete after the administered tariquidar dose.

Lateralization is a well described aspect of the human brain. A plethora of morphological, cytological and functional studies describes hemispheric asymmetry in auditory and language areas. However, no study has reported cortical lateralization in the healthy human brain in vivo on the level of neurotransmitter receptors and in relation to functional organization so far. In this study, we assessed the distribution of the main inhibitory serotonergic receptor (the 5-HT1A receptor) and analyzed its regional binding with regard to hemisphere, sex and plasma levels of sex steroid hormones (testosterone, estradiol, progesterone). We quantified the 5-HT1A receptor binding potential by positron emission tomography (PET) using the highly selective and specific radioligand [carbonyl-11C]WAY-100635 and measured hormone levels in thirty-four (16 females, 18 males) healthy right-handed subjects. The obtained data were analyzed in an automated region of interest (ROI) based approach investigating 14 auditory, language and limbic areas. We found significantly higher 5-HT1A receptor binding in the superior and middle frontal gyri of the right hemisphere, the triangular and orbital parts of the inferior frontal gyrus, the supramarginal gyrus, the superior gyrus of the temporal pole and the middle temporal gyrus. Regions of the primary and secondary auditory cortex (Heschl's gyrus and superior temporal gyrus) and the Rolandic operculum displayed significantly higher receptor binding in the left hemisphere. 5-HT1A receptor binding was 1.8-2.9% higher in right frontal ROIs and 2-3.6% higher in left primary and secondary auditory regions. There was no hemispheric difference in 5-HT(1A) receptor binding in the hippocampus, amygdala, and insula. Post-hoc testing suggested that lateralization of 5-HT1A receptor binding differed between the sexes in the triangular part of the inferior frontal gyrus. For the first time, this PET study shows lateralization of the main inhibitory receptor of the serotonergic system in functionally asymmetric organized regions of the healthy human brain in vivo.

There is an increasing interest in the underlying mechanisms of the antidepressant and anxiolytic treatment effect associated with changes in serotonergic neurotransmission after treatment with selective serotonin (5-HT) reuptake inhibitors (SSRIs) in humans. The 5-HT(1A) receptor is known to play a crucial role in the pathophysiology of affective disorders, and altered 5-HT(1A) receptor binding has been found in anxiety patients. SSRI treatment raises the 5-HT level in the synaptic cleft and might change postsynaptic receptor densities. Therefore, our study in patients suffering from anxiety disorders investigated the effects of long-term treatment with escitalopram on the 5-HT(1A) receptor. A longitudinal positrone emission tomography (PET) study in 12 patients suffering from anxiety disorders was conducted. Two dynamic PET scans were performed applying the selective 5-HT(1A) receptor antagonist [carbonyl-(11)C]WAY-100635. Eight regions of interest were defined a priori (orbitofrontal cortex, amygdala, hippocampus, subgenual cortex, anterior and posterior cingulate cortex, dorsal raphe nucleus and cerebellum as reference). After the baseline PET scan, patients were administered escitalopram (average dose of 11.2+/-6.0 mg day(-1)) for a minimum of 12 weeks. A second PET scan was conducted after 109+/-27 days. 5-HT(1A) receptor binding potentials in 12 patients were assessed by PET applying the Simplified Reference Tissue Model.There was a significant reduction in the 5-HT(1A) receptor binding potential after a minimum of 12 weeks of escitalopram treatment in the hippocampus (P=0.006), subgenual cortex (P=0.017) and posterior cingulate cortex (P=0.034). The significance of the hippocampus region survived the Bonferroni-adjusted threshold for multiple comparisons. These PET data in humans in vivo demonstrate a reduction of the 5-HT(1A) binding potential after SSRI treatment.

Purpose (R)-[C-11]verapamil is a new PET tracer for P-glycoprotein-mediated transport at the blood-brain barrier. For kinetic analysis of (R)-[C-11]verapamil PET data the measurement of a metabolite-corrected arterial input function is required. The aim of this study was to assess peripheral (R)-[C-11]verapamil metabolism in patients with temporal lobe epilepsy and compare these data with previously reported data from healthy volunteers.Methods Arterial blood samples were collected from eight patients undergoing (R)-[C-11]verapamil PET and selected samples were analysed for radiolabelled metabolites of (R)-[C-11]verapamil by using an assay that measures polar N-demethylation metabolites by solid-phase extraction and lipophilic N-dealkylation metabolites by HPLC.Results Peripheral metabolism of (R)-[C-11]verapamil was significantly faster in patients compared to healthy volunteers (AUC of (R)-[C-11]verapamil fraction in plasma: 29.4 +/- 3.9 min for patients versus 40.8 +/- 5.0 min for healthy volunteers; p Conclusions Faster metabolism of (R)-[C-11]verapamil in epilepsy patients may be caused by hepatic cytochrome P450 enzyme induction by antiepileptic drugs. Based on these data caution is warranted when using an averaged arterial input function derived from healthy volunteers for the analysis of patient data. Moreover, our data illustrate how antiepileptic drugs may decrease serum levels of concomitant medication, which may eventually lead to a loss of therapeutic efficacy.

Since the late 1980s, cocaine analogues based on the phenyltropane structure, such as [(11)C]CFT and [(123)I]beta-CIT have been used for the imaging of the dopamine transporter. FE@CIT (fluoropropyl ester) and FP-CIT (N-fluoropropyl derivative) are further analogues. The aim of this study was to (1) evaluate and compare the metabolic stability of beta-CIT, FP-CIT and FE@CIT against carboxyl esterases and (2) evaluate selectivity of [(18)F]FE@CIT compared to [(123)I]beta-CIT and [(123)I]FP-CIT using autoradiography.In vitro enzymatic hydrolysis assays were performed using different concentrations of beta-CIT, FE@CIT and FP-CIT with constant concentrations of carboxyl esterase. Autoradiography was performed on coronal 20-microm rat brain sections incubated with different radioactivity concentrations of [(123)I]beta-CIT, [(123)I]FP-CIT or [(18)F]FE@CIT and, additionally, with 3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile [serotonin transporter (SERT)] and nisoxetine [norepinephrine transporter (NET)] for blocking experiments.In vitro assays showed Michaelis-Menten constants of 175 micromol (beta-CIT), 183 micromol (FE@CIT) and 521 micromol (FP-CIT). Limiting velocities were 0.1005 micromol/min (beta-CIT), 0.1418 micromol/min (FE@CIT) and 0.1308 micromol/min (FP-CIT). This indicates a significantly increased stability of FP-CIT, whereas carboxyl esterase stability of beta-CIT and FE@CIT showed no significant difference. Autoradiographic analyses revealed a good correlation between dopamine transporter (DAT)-rich regions and the uptake pattern of FE@CIT. Blocking experiments showed a higher DAT selectivity for [(18)F]FE@CIT than for the other two tracers.We found that (1) the metabolic stability of FE@CIT was comparable to that of beta-CIT, whereas FP-CIT showed higher resistance to enzymatic hydrolysis; and (2) the overall uptake pattern of [(18)F]FE@CIT on brain slices was comparable to that of [(123)I]beta-CIT and [(123)I]FPCIT. After blocking of NET and SERT binding, a significantly higher DAT selectivity was observed for [(18)F]FE@CIT. Hence, [(18)F]FE@CIT may be of interest for further clinical application.

The aim of this study was to evaluate the value of [11C] methionine (MET) and [18F] fluorodeoxyglucose (FDG) PET in the follow-up of glioblastoma multiforme (GBM).After surgical and/or conservative treatment, 28 patients (pts) with GBM underwent FDG and MET PET on average 12.7 months after the diagnosis had been established. Scans were evaluated visually and by calculating the maximal tumor SUV as well as the ratio of tumor vs. contralateral region (RTu). The degree of tracer uptake was compared with survival time, disease duration and MRI findings.The mean overall duration of survival was 12.7 months. The patients were divided into two groups: those that survived less than 12 months and those that survived longer than 12 months. Focally increased uptake was revealed by MET PET in 24 patients and by FDG PET in 2 patients. On MRI scans, viable tumor tissue was suspected in 18 patients. No correlations were registered between FDG/MET uptake and survival time or disease duration respectively; Kaplan-Meier calculations were negative in this regard. Similarly, negative results were obtained in subgroups of patients who had undergone microsurgical resection and whose disease was at least of 6 months' duration, and additionally in a subgroup who had undergone their last treatment longer than 6 months ago. With respect to survival groups, a positive MET PET was associated with a sensitivity of 86% and a specificity of 8%. SUV and RTu values did not differ between patients with positive or negative MRI results.In this study FDG PET seems to be of limited value in the work-up of recurrent GBM because of its lower sensitivity than MET PET and the fact that it allows no prediction of the outcome. MET PET visualizes viable tumor tissue without adding any prognostic information and appears to be in no way superior to conventional imaging.

Regional overexpression of the multidrug transporter P-glycoprotein (P-gp) in epileptic brain tissue may lower target site concentrations of antiepileptic drugs and thus contribute to pharmacoresistance in epilepsy. We used the P-gp substrate R-[(11)C]verapamil and positron emission tomography (PET) to test for differences in P-gp activity between epileptogenic and nonepileptogenic brain regions of patients with drug-resistant unilateral temporal lobe epilepsy (n = 7). We compared R-[(11)C]verapamil kinetics in homologous brain volumes of interest (VOIs) located ipsilateral and contralateral to the seizure focus.Among different VOIs, radioactivity was highest in the choroid plexus. The hippocampal VOI could not be used for data analysis because it was contaminated by spill-in of radioactivity from the adjacent choroid plexus. In several other temporal lobe regions that are known to be involved in seizure generation and propagation ipsilateral influx rate constants K(1) and efflux rate constants k(2) of R-[(11)C]verapamil were descriptively increased as compared to the contralateral side. Parameter asymmetries were most prominent in parahippocampal and ambient gyrus (K(1), range: -3.8% to +22.3%; k(2), range: -2.3% to +43.9%), amygdala (K(1), range: -20.6% to +31.3%; k(2), range: -18.0% to +38.9%), medial anterior temporal lobe (K(1), range: -8.3% to +14.5%; k(2), range: -14.5% to +31.0%) and lateral anterior temporal lobe (K(1), range: -20.7% to +16.8%; k(2), range: -24.4% to +22.6%). In contrast to temporal lobe VOIs, asymmetries were minimal in a region presumably not involved in epileptogenesis located outside the temporal lobe (superior parietal gyrus, K(1), range: -3.7% to +4.5%; k(2), range: -4.2% to +5.8%). In 5 of 7 patients, ipsilateral efflux (k(2)) increases were more pronounced than ipsilateral influx (K(1)) increases, which resulted in ipsilateral reductions (10%-26%) of R-[(11)C]verapamil distribution volumes (DV). However, for none of the examined brain regions, any of the differences in K(1), k(2) and DV between the epileptogenic and the nonepileptogenic hemisphere reached statistical significance (p0.05, Wilcoxon matched pairs test).Even though we failed to detect statistically significant differences in R-[(11)C]verapamil model parameters between epileptogenic and nonepileptogenic brain regions, it cannot be excluded from our pilot data in a small sample size of patients that regionally enhanced P-gp activity might contribute to drug resistance in some patients with temporal lobe epilepsy.

Angiography of patients with typical chest pain reveals normal epicardial coronary arteries in about 20%. Coronary flow reserve (CFR) determination is an elaborate, but helpful, task, as only the evidence of microvascular disease enables appropriate therapy. We prospectively evaluated the incidence of a dysfunctional microcirculation and searched for predictive parameters of a reduced CFR.In 79 consecutive patients (52 females, 27 males) with typical angina and a normal angiogram and 10 control subjects (6 females, 4 males), CFR was measured by 13N-ammonia rest/dipyridamole PET and correlated with clinical parameters individually and summarized as the number of risk factors (NRF) using an elaborated cardiac risk factor score.Sixty-five percent of patients had a reduced CFR (CFR2.5). CFR correlated with NRF (r = 0.55, P0.001), systolic blood pressure (r = 0.46, P0.001), interventricular septal thickness (r = 0.33, P0.01), and age (r = 0.25, P = 0.02). Eighty-five percent of patients with a high risk factor score (NRFor = 5) had a reduced CFR. In contrast, 100% of our patients with a low risk factor score (NRF2) presented a normal CFR. In total, 55% of our patients could be allocated to either one of these groups.In about two thirds of patients, anginal pain can be explained by a reduced CFR. Risk factors have a cumulative negative effect on CFR. A clinical cardiac risk factor analysis enables estimation of individual probability of microvascular dysfunction in a significant proportion of these patients. However, CFR measurements are recommended for those with an intermediate NRF.

The aim of the study was to evaluate the possible changes in CD4+ and CD8+ T-cell cytokine production patterns in Hashimoto's thyroiditis (HT) with elevated calcitonin (CT). Fourteen consecutive patients with verified HT were included in the present study. Patients were divided into two groups. Group I: 7 HT patients with elevated CT levels (10 pg/ml); Group II: 7 HT patients with CT levels10 pg/ml). All patients underwent intracellular cytokine detection in CD4+ and CD8+ T-cells of peripheral blood mononuclear cells (PBMC) by flow cytometry. Patients with elevated CT levels (group I) had significantly higher percentages of CD8+ cells producing IFN-gamma compared to healthy donors. A detailed analysis of cytokine production patterns revealed that this was accompanied by an increased frequency of single IFN-gamma positive cells, i.e., cells not expressing most of the other cytokines tested. Similarly, patients in group I also showed higher percentages of CD8+ TNF-alpha positive cells than healthy donors. In this case, cells co-expressing TNF-alpha and IFN-gamma were found at significantly higher frequencies. No increase in Th1 type cytokines, such as IFN-gamma or TNF-alpha, was detectable in CD4+ T-cells. In contrast, CD4+ T-cells from group I patients showed significantly higher percentages of cells producing Th2 cytokines, such as IL-4 or IL-13. The lack of increased Th1 cytokine production accompanied by an increased Th2 cytokine production seems to be a special feature of HT patients with elevated CT levels that may reflect a pathogenetic mechanism for tumor initiation.

The measurement of basal serum calcitonin (CT) in patients with evidence of Hashimoto's thyroiditis (HT) has been proposed in a recent study demonstrating an increased prevalence of elevated basal and stimulated CT. The aim of this study was to evaluate the frequency and relevance of elevated CT levels in HT. The basal sera CT were measured in 568 consecutive HT patients using a chemiluminescent immuno-assay. Whenever the serum CT was10 pg/ml, a pentagastrin (PG) stimulation test was performed. Two patients with abnormal/pathological PG tests were identified. Total thyroidectomy and lymph node dissection revealed for the first patient medullary thyroid carcinoma (MTC) and for the second patient C cell hyperplasia (CCH), together with papillary thyroid carcinoma. Our data showed a low prevalence of MTC and its premalignant condition CCH in HT patients; nevertheless, the patient with MTC presented lymph node metastasis. The fact that both cases presented without evidence of nodular thyroid disease highlights the persistent diagnostic dilemma of CT screening programs.

Purpose To assess the clinical value of computed tomography (CT) and magnetic resonance imaging (MRI) image fusion with 11C-acetate (AC) positron emission tomography (PET) imaging for detection and exact location of clinically occult recurrences. Patients and Methods Fifty prostate cancer patients with elevated/increasing serum prostate-specific antigen levels after radical therapy underwent whole-body AC PET. Uptake was initially interpreted as normal, abnormal, or equivocal. In case of abnormal or equivocal uptake, additional conventional imaging techniques, such as CT, MRI, and bone scans, were performed. To precisely define the anatomic location of abnormal uptake and to improve characterization of equivocal lesions, a software-assisted image fusion (CT-PET, MRI-PET) was performed and evaluated as site-by-site analysis of 51 abnormal (n = 37) or equivocal (n = 14) sites of all 50 patients. In 17 patients, additional histopathologic evaluation was available. Results In five (10%), 13 (26%), and 32 (64%) of the 50 patients, AC PET studies demonstrated AC uptake judged as normal, equivocal, and abnormal, respectively. Image fusion changed characterization of equivocal lesions as normal in five (10%) of 51 sites and abnormal in nine (18%) of 51 sites. It precisely defined the anatomic location of abnormal uptake in 37 (73%) of 51 sites. AC PET findings did influence patient management in 14 (28%) of 50 patients. Conclusion Retrospective fusion of AC PET and CT/MRI is feasible and seems to be essential for final diagnosis. This is particularly true in patients with AC uptake in the prostate region.

Background Approximately 10–30% of patients with typical chest pain present normal epicardial coronaries. In a proportion of these patients, angina is attributed to microvascular dysfunction. Previous studies investigating whether angina is the result of abnormal resting or stress perfusion are controversial but limited by varying inclusion criteria. Therefore, we investigated whether microvascular dysfunction in these patients is associated with perfusion abnormalities at rest or at stress. Patients and methods In 58 patients (39 female, 19 male, mean age 58 ± 10 years) with angina and normal angiogram as well as 10 control patients with atypical chest pain and normal coronaries (six female, four male, mean age 53 ± 11 years) myocardial blood flow (MBF) was measured at rest and under dipyridamole using 13N–ammonia PET. Resting MBF and coronary flow reserve (CFR) as the ratio of hyperaemic to resting MBF were corrected for rate – pressure – product (RPP): normalized resting MBF (MBFn) = MBF × 10 000/RPP and CFRn = CFR × RPP/10 000. Results Sixteen/58 patients had a normal CFRn (= 2·5; group I; CFRn: 3·1 ± 0·88); the same as the controls (CFRn: 3·3 ± 0·74). Forty-two/58 patients presented a reduced CFRn (group II; CFRn: 1·78 ± 0·57). Group II had both a higher MBFn (group II: 1·30 ± 0·33 vs. Group I: 1·03 ± 0·26; P

Background Results from studies in serotonin-1A (5-HT 1A ) knockout mice and previous positron emission tomography (PET) studies in humans imply a role for 5-HT 1A receptors in normal state anxiety as well as in certain anxiety disorders. The objective of this study was to investigate 5-HT 1A receptor binding potential (BP) in social anxiety disorder (SAD). Methods Using PET and [carbonyl- 11 C]WAY-100635, we compared a homogeneous group of 12 unmedicated, male SAD patients with 18 healthy control subjects (HC). A multivariate ANOVA with all regional BP values as dependent variables, age and four radiochemical variables as covariates was performed. Results We found a significantly lower 5-HT 1A BP in several limbic and paralimbic areas but not in the hippocampus (p = .234) of SAD patients. The difference in 5-HT 1A binding was most significant in the amygdala (−21.4%; p=.003). There was also a more than 20% lower 5-HT 1A BP of SAD patients in the anterior cingulate cortex (p = .004), insula (p = .003), and dorsal raphe nuclei (p = .030). Conclusions The lower 5-HT 1A binding in the amygdala and mesiofrontal areas of SAD patients is consistent with 1) preclinical findings of elevated anxiety in 5-HT 1A knockout mice, 2) a previous PET study in healthy volunteers showing an inverse correlation between 5-HT 1A BP and state anxiety, and 3) another human PET study in patients with panic disorder showing reduced 5-HT 1A binding, thus corroborating the potential validity of 5-HT 1A receptors as targets in the treatment of human anxiety disorders.

This work describes a microdosing study with an investigational, carbon 11-labeled antiamyloid drug, 1,1'-methylene-di-(2-naphthol) (ST1859), and positron emission tomography (PET) in healthy volunteers (n = 3) and patients with Alzheimer's disease (n = 6). The study aimed to assess the distribution and local tissue pharmacokinetics of the study drug in its target organ, the human brain. Before PET studies were performed in humans, the toxicologic characteristics of ST1859 were investigated by an extended single-dose toxicity study according to guidelines of the Food and Drug Administration and European Medicines Agency, which are relevant for clinical trials with a single microdose. After intravenous bolus injection of 341 +/- 21 MBq [(11)C]ST1859 (containing

Summary Background Mesalazine (5-aminosalicylic acid, 5-ASA) containing formulations represent a cornerstone in the treatment of inflammatory bowel diseases. A novel formulation with an Eudragit L/S mixture coating has been developed to provide selective release of 5-ASA to the ileo-caecal region and the colon. Aim To determine the release of 5-ASA during the gastrointestinal transit. Methods A single oral dose of mesalazine EC 500 mg gastroresistant tablets (Asamax) was administered to eight healthy male volunteers. Gastrointestinal transit and tablet disintegration were monitored by scintigraphy. 5-ASA release was verified by assessing plasma pharmacokinetics. Results Initial tablet disintegration was observed 5.65 ± 0.86 h after dosing, corresponding to the detection of 5-ASA in plasma. This occurred in the ileo-caecal region in three subjects and the ascending colon in the remaining five. The relative percentage of 5-ASA absorption was more pronounced in the ascending colon (41 ± 27.4%) than the ileo-caecal region (6.6 ± 9.2%). Conclusion This mesalazine EC gastroresistant tablets release locally active 5-ASA specifically in the ileo-caecal region and the ascending colon.

The aims of the study were to: (1) evaluate the gastrointestinal transit, release and absorption of budesonide from tablets with a new multimatrix formulation (MMX) designed to release the drug throughout the whole colon, and (2) assess the influence of food on budesonide bioavailability.Two phase I studies, each comprising 12 healthy males, were performed. Gastrointestinal transit of (153)Sm-labelled tablets containing 9 mg budesonide was evaluated by means of pharmaco-scintigraphy. The effect of food was tested by comparing plasma pharmacokinetics after intake of a high fat and high calorie breakfast with fasting controls.(153)Sm-labelled tablets reached the ascending colon after a mean +/- SD 9.8 +/- 6.9 h. Initial tablet disintegration was observed in the ileum in 42% and the ascending and transverse colon in 33% of subjects. Ninety-six per cent of the dose was absorbed into the systemic circulation during passage through the whole colon including the sigmoid. Food significantly decreased C(max) values from 1429 +/- 1014 to 1040 +/- 601 pg mL(-1) (P = 0.028) and AUC values from 14 814 +/- 11 254 to 13 486 +/- 9369 pg h(-1) mL(-1) (P = 0.008). Mean residence time and t(max) increased by 12-29%. There was no drug accumulation after 1 week of once daily oral administration of budesomide.MMX-budesonide tablets appear suitable for targeted colonic drug delivery. Transit parameters and low systemic bioavailability warrant further studies with the new formulation.

The purpose of this study was to evaluate myocardial electrocardiography (ECG)-gated 13N-ammonia (13N-NH3) PET for the assessment of cardiac end-diastolic volume (EDV), cardiac end-systolic volume (ESV), left ventricular (LV) myocardial mass (LVMM), and LV ejection fraction (LVEF) with gated 18F-FDG PET as a reference method.ECG-gated 13N-NH3 and 18F-FDG scans were performed for 27 patients (23 men and 4 women; mean+/-SD age, 55+/-15 y) for the evaluation of myocardial perfusion and viability. For both 13N-NH3 and 18F-FDG studies, a model-based image analysis tool was used to estimate endocardial and epicardial borders of the left ventricle on a set of short-axis images and to calculate values for EDV, ESV, LVEF, and LVMM.The LV volumes determined by 13N-NH3 and 18F-FDG were 108+/-60 mL and 106+/-63 mL for ESV and 175+/-71 mL and 169+/-73 mL for EDV, respectively. The LVEFs determined by 13N-NH3 and 18F-FDG were 42%+/-13% and 41%+/-13%, respectively. The LVMMs determined by 13N-NH3 and 18F-FDG were 179+/-40 g and 183+/-43 g, respectively. All P values were not significant, as determined by paired t tests. A significant correlation was observed between 13N-NH3 imaging and 18F-FDG imaging for the calculation of ESV (r=0.97, SEE=14.1, P0.0001), EDV (r=0.98, SEE=15.4, P0.0001), LVEF (r=0.9, SEE=5.6, P0.0001), and LVMM (r=0.93, SEE=15.5, P0.0001).Model-based analysis of ECG-gated 13N-NH3 PET images is accurate in determining LV volumes, LVMM, and LVEF. Therefore, ECG-gated 13N-NH3 can be used for the simultaneous assessment of myocardial perfusion, LV geometry, and contractile function.

Because many drugs possess an intracellular site of action, the knowledge of intracellular concentration-time profiles is desirable. In the present study, PET, which measures total (i.e., intracellular, extracellular, and intravascular) concentrations of radiolabeled drugs in tissue, and microdialysis, which determines unbound drug concentrations in the extracellular space fluid of tissue, were combined to describe the intracellular pharmacokinetics of a model compound--that is, the (18)F-labeled antibiotic (18)F-ciprofloxacin--in vivo in humans.Ten healthy male volunteers received a mixture of 687 +/- 50 MBq of (18)F-ciprofloxacin and 200 mg of unlabeled ciprofloxacin as an intravenous bolus infusion over 10 min. The pharmacokinetics of ciprofloxacin in skeletal muscle tissue were assessed by means of combined PET and in vivo microdialysis for 5 h after drug administration. A 3-compartment pharmacokinetic model was fitted to the tissue concentration-time profiles of ciprofloxacin measured by PET to estimate the rate constants of ciprofloxacin uptake and transport.In muscle tissue, mean total and extracellular peak concentration (C(max)) values of ciprofloxacin of 1.8 +/- 0.4 microg/mL and 0.7 +/- 0.2 microg/mL were attained at 95 +/- 34 min and 48 +/- 20 min after drug administration, respectively. The extracellular-to-intracellular exchange appeared to be very fast, with an estimated rate constant k(3) of 1.69 +/- 0.25 min(-1). An intracellular-to-extracellular concentration ratio (C(intra)/C(extra)) of 3.2 +/- 0.8 was reached at 110 min after injection and followed by sustained intracellular retention of the antibiotic for the remainder of the experiment. The predicted extracellular concentration-time profiles from the compartmental modeling were in good agreement with the measured microdialysis data.The results obtained in the present study were in accordance with previous in vitro data describing cellular ciprofloxacin uptake and retention. The presently used PET/microdialysis combination might be useful during research and development of new drugs, for which knowledge of intracellular concentrations is of interest.

OBJECTIVE Cytokines produced by cytotoxic T cells or autoantibodies lead to thyroid cell damage and/or cell death in Hashimoto's thyroiditis (HT). Anti-TPO autoantibodies (TPOAb) are the most frequently represented autoantibodies in the sera of patients with HT. Data describing the quantitative correlation between TPOAb titre and cytokine pattern are missing so far. To our knowledge this is the first study systematically evaluating the correlation of possible parameters of disease activity such as changes in CD4 and CD8 T-cell cytokine production and of TPOAb titre. METHODS Twenty-four consecutive patients (aged 29-58) with verified HT under levothyroxine therapy were included in the present study. The patients were divided into two groups. Group I: 12 HT patients with a high TPOAb titre (> 1000 U/ml), group II: 12 HT patients with a low TPOAb titre (< 100 U/ml). All patients underwent intracellular cytokine detection in CD4 and CD8 T cells of peripheral blood mononuclear cells (PBMC) by flow cytometry. Twelve healthy volunteers matched in sex and age consisted the control group (group III). RESULTS T cells from patients with a high TPOAb titre (group I) had significantly higher percentages of cells producing IFN-gamma compared to healthy donors (group III). A detailed analysis of cytokine production patterns revealed that this was accompanied by an increased frequency of single IFN-gamma positive cells, i.e. cells not expressing other cytokines tested, such as IL-2, IL-4, IL-5, IL-6, IL-10, IL-13 or TNF-beta. Similarly, patients in group I also showed higher percentages of TNF-alpha positive cells than healthy donors (group III). In this case, cells expressing TNF-alpha alone as well as cells coexpressing TNF-alpha and IFN-gamma were found at significantly higher frequencies. On the other hand, cytokine production patterns of patients with a low TPOAb titre (group II) showed significant difference neither to patients of group I nor to healthy donors (group III). CONCLUSION Taken together, we were able for the first time to demonstrate that high TPOAb titre correlates with increased frequencies of T cells producing Th/Tc1 cytokines, probably responsible for thyroid cell damage and/or death in Hashimoto's thyroiditis.