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Abstract: Functional information provided by PET tracers together with the superior image quality and the better data quantification by PET technology had a changing effect on the significance of nuclear medicine in medical issues. Recently introduced hybrid PET/CT systems together with the introduction of novel PET radiopharmaceuticals have contributed to the fact that nuclear medicine has become a growing diagnostic impact on endocrinology. In this review imaging strategies, different radiopharmaceuticals including the basic mechanism of their cell uptake, and the diagnostic value of PET and PET/CT in endocrine tumours except differentiated thyroid carcinomas will be discussed. [Copyright &y& Elsevier]

Objective. Statins are potent inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase and widely used to treat hyperlipidaemia. Apart from their direct lipid-lowering effects, statins may also influence lipid metabolism through modulation of low-density lipoprotein (LDL) receptors. Basophils and mast cells have been reported to express LDL receptors and have been implicated in atherogenesis. The aim of this study was to investigate the effects of statins on the interactions of 125I-LDL with purified primary human blood basophils, a human basophil cell line, KU812, and a human mast cell line, HMC-1. Methods. Direct binding experiments were carried out with the primary basophils and KU812 as well as HMC-1 cells before and after pretreatment of the cells with atorvastatin, simvastatin, or cerivastatin. The effects of these three statins on the LDL-uptake and degradation as well as on thymidine incorporation in the cells were also studied. Results. Primary basophils, HMC-1 and KU812 cells expressed two classes of LDL binding sites. Exposure to atorvastatin, simvastatin or cerivastatin increased significantly (P<0.05) the number of 125I-LDL binding sites on primary basophils and HMC-1 as well as KU812 cells. The effects of the statins were dose dependent. The statins also enhanced the uptake and degradation of LDL in primary basophils, HMC-1 and KU812 cells. The increase in the number of LDL binding sites induced by statins was abolished by mevalonic acid (200 μmol/l). Statins had no effect on the thymidine incorporation into the cells in an unstimulated condition. Conclusion. Our results provide evidence for the upregulation of LDL binding sites on human basophils and mast cells by statins. We hypothesise that effects of statins on the lipid metabolism might also involve basophils and mast cells. [ABSTRACT FROM AUTHOR]

Background: Since Nichols Institute Diagnostics (NID) ended production of their automated calcitonin immunoassay, evaluation of an alternative calcitonin assay was necessary. Methods: Calcitonin measured by the NID procedure was compared with a test from Diagnostic Products Corporation (DPC). Calcitonin was also measured by assays from DiaSorin (DS) and Scantibodies (SC). Results: In 187 samples, detection failed either by NID (39%) or DPC (96%) assay; in 35% of samples, the tests agreed for non-measurable calcitonin. The regression line DPC=0.78×NID−0.3 (r=0.998) fitted results from 236 samples with detectable calcitonin. A linear relationship, albeit with scattering at low concentrations, was observed. Importantly, stimulation by pentagastrin above basal calcitonin concentrations yielded similar results with both assays. Comparisons (DPC=0.80×DS−3.4 and DPC=0.81×SC−1.1) confirmed an aberrant calibration of the DPC test. To overcome the method bias, we propose a multiplication factor of 0.8 to convert NID to DPC results. Conclusions: Apparently due to non-specific effects, the DS and SC assays produced calcitonin results in samples from completely thyroidectomized patients, while the DPC assay correctly failed to detect calcitonin. Thus, the DPC assay on an Immulite® 2000 analyzer may be used as a more accurate substitute for NID if the different calibration is noted. Clin Chem Lab Med 2007;45:662–6. [ABSTRACT FROM AUTHOR]

The current study aimed to determine the optimum diagnostic imaging technique out of magnetic resonance imaging (MRI), 18F‑fludeoxyglucose positron emission tomography/computed tomography ([18F] FDG‑PET/CT, otherwise known as PET/CT) and [18F] FDG‑PET/MRI (otherwise known as PET/MRI) for the pelvic lymph node staging (N‑staging) of untreated cervical carcinoma (CC). A total of 27 patients were included in the present study. All patients had undergone pre‑treatment with PET/CT and MRI ≤45 days prior to undergoing a lymphadenectomy. The results from PET (separated from PET/CT), MRI and the statistically combined results of (virtual) PET/MRI were compared to those from histological analyses (the gold standard). A per‑patient‑based analysis of the detection of pelvic lymph node metastases indicated that PET/MRI had a sensitivity of 64%. The specificity of PET/CT and MRI were 69 and 62%, respectively. The positive predictive value (PPV) was 69 and 64% for PET/CT and MRI, respectively. The negative predictive value (NPV) was 64 and 62% for PET/CT and MRI, respectively. The sensitivity of the PET‑guided PET/MRI and the MRI‑guided PET/MRI was 64% for both. The specificity of the PET‑guided PET/MRI and the MRI‑guided PET/MRI was 77 and 62%, respectively. The PPV was 75% for PET‑guided PET/MRI and 64% for MRI‑guided PET/MRI, and the NPV was 67 and 62%, respectively. PET/CT and the virtual PET/MRI exhibited the same low sensitivity (64%). PET/MRI exhibited slightly better results than PET/CT regarding specificity (77 vs. 69%, respectively), PPV (75 vs. 69%, respectively) and NPV (67 vs. 64%, respectively). The results of the present study suggested that PET/CT and MRI are not optimal diagnostic modalities, and that PET/MRI does not necessarily lead to better results than PET/CT, in the pelvic N‑staging of CC. [ABSTRACT FROM AUTHOR]

Abstract: The intention for the present study was to implement a microfluidic set-up for N-11C-methylations in a flow-through microreactor device with [11C]DASB as model-compound and [11C]CH3I and [11C]CH3OTf, respectively, as 11C-methylation agents. Due to an observed “aging” effect of the 11C-methylation agents'' solution, this goal was not achieved. Nevertheless, based on these observations, the time consumption for the vessel-based routine production of [11C]DASB was reduced (34±1min) and RCY was increased to 45.1±4.6% (EOB; 5.2±0.95GBq EOS). [Copyright &y& Elsevier]

Abstract: Introduction: Our aim was the optimization of radiochemical parameters for the microfluidic preparation of [18F]altanserin. The four main parameters evaluated were (1) precursor concentration, (2) reaction temperature, (3) bolus flow rate through the microreactor and (4) bolus volume. Methods: For the determination of optimal reaction conditions within a flow-through microreactor synthesizer, 5–400 μL of precursor and dried [18F]fluoride solution were simultaneously pushed through the temperature-controlled reactor (180–220°C) with defined bolus flow rates of 10–60 μL/min. Radiochemical incorporation yields (RCIYs) were examined using a thin layer chromatography (TLC) set-up and radio- high-performance liquid chromatography (HPLC). Results: Optimum reaction parameters for the microfluidic set-up were determined as following: 220°C, 5–10 μL/min pump rate per reactant (10–20 μL/min reaction overall flow rate) and 2mg/mL precursor concentration in the reaction mixture. Applying these optimized conditions, RCIYs of 53.7±7.9 were observed for scaled-up preparations. A positive “bolus effect” was observed: applying higher reaction volume resulted in increased RCIYs. Conclusion: This study proved that the reaction bolus volume is an essential parameter influencing the RCIY of [18F]altanserin. A possible explanation is the inhomogeneous distribution within the reaction volume probably caused by diffusion at the bolus interface. This important finding should be considered an important variable for the evaluation of all novel radiotracers labeled using a flow-through reactor device. [Copyright &y& Elsevier]

Background: The association of subclinical hypothyroidism (SCH) with increased risk for cardiovascular disease is still controversial. This study aimed to examine coronary vascular reactivity by positron emission tomography (PET) in asymptomatic patients with SCH before and after levothyroxine (LT4) supplementation. Methods: Ten patients (7 women and 3 men; mean age 43±15 years) with untreated autoimmune SCH, defined by elevated levels of thyroid-stimulating hormone (mean TSH: 16.9±11.3 μU/mL), normal levels of free thyroxine (0.9±0.1 μg/mL), free triiodothyronine (3.2±0.4 pg/mL), and positive thyroid peroxidase antibodies were studied. Eight euthyroid subjects with similar low-risk cardiovascular risk profile served as controls. Myocardial blood flow (MBF) and coronary flow reserve (CFR) were quantitatively assessed with rest/stress N-13 ammonia PET at baseline and after 6 months of LT4 replacement therapy (given only to patients). Results: At baseline, stress MBF and CFR corrected (c) for rate pressure product (RPP) and myocardial vascular resistance (MVR) during stress were significantly reduced in SCH compared with controls (stress MBF: 2.87±0.93 vs. 4.79±1.16 mL/g/min, p=0.003; CFR: 2.6±0.73 vs. 4.66±1.38, p=0.004; MVR: 40.14±18.76 vs. 20.47±6.24 mmHg/mL/min, p=0.02). Supplementation therapy with LT4 normalized TSH in all subjects and was associated with an increase in CFR (2.6±0.73 vs. 3.81±1.19, p=0.003) and with a tendency toward a decrease in MVR. Differences in CFR between SCH and controls were also seen after correction of resting MBF for RPP. Conclusions: In asymptomatic subjects with SCH due to thyroid autoimmunity, coronary microvascular function is impaired and improves after supplementation with LT4. This may partially explain the increased cardiovascular risk attributed to SCH. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Recently, first applications of microfluidic principles for radiosyntheses of positron emission tomography compounds were presented, but direct comparisons with conventional methods were still missing. Therefore, our aims were (1) the set-up of a microfluidic procedure for the preparation of the recently developed adenosine A3-receptor tracers [18F]FE@SUPPY [5-(2-[18F]fluoroethyl)2,4-diethyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate] and [18F]FE@SUPPY:2 [5-ethyl-2,4-diethyl-3-((2-[18F]fluoroethyl)sulfanylcarbonyl)-6-phenylpyridine-5-carboxylate] and (2) the direct comparison of reaction conditions and radiochemical yields of the no-carrier-added nucleophilic substitution with [18F]fluoride between microfluidic and conventional methods. Methods: For the determination of optimal reaction conditions within an Advion NanoTek synthesizer, 5–50 μl of precursor and dried [18F]fluoride solution were simultaneously pushed through the temperature-controlled reactor (26°C–180°C) with defined reactant bolus flow rates (10–50 μl/min). Radiochemical incorporation yields (RCIYs) and overall radiochemical yields for large-scale preparations were compared with data from conventional batch-mode syntheses. Results: Optimal reaction parameters for the microfluidic set-up were determined as follows: 170°C, 30-μl/min pump rate per reactant (reaction overall flow rate of 60 μl/min) and 5-mg/ml precursor concentration in the reaction mixture. Applying these optimized conditions, we observed a significant increase in RCIY from 88.2% to 94.1% (P<.0001, n≥11) for [18F]FE@SUPPY and that from 42.5% to 95.5% (P<.0001, n≥5) for [18F]FE@SUPPY:2 using microfluidic instead of conventional heating. Precursor consumption was decreased from 7.5 and 10 mg to 1 mg per large-scale synthesis for both title compounds, respectively. Conclusion: The direct comparison of radiosyntheses data applying a conventional method and a microfluidic approach revealed a significant increase of RCIY using the microfluidic approach. [Copyright &y& Elsevier]

Abstract: Introduction: Carboxylesterases (CES) play a very important role in the hydrophilic biotransformation of a huge number of structurally diverse drugs and especially play a leading part in the catabolic pathway of carboxylesters or thioesters. Hence, the aim of the present study was the comparison of the in vitro stability of methyl- and ethylesters with fluoroethylesters. Methods: We incubated methyl 3β-(4-iodophenyl)tropane-2β-carboxylate (β-CIT)/2-fluoroethyl 3β-(4-iodophenyl)tropane-2β-carboxylate (FE@CIT), methyl 1-(1-phenylethyl)-1H-imidazole-5-carboxylate (MTO)/ethyl 1-(1-phenylethyl)-1H-imidazole-5-carboxylate (ETO)/2-fluoroethyl 1-(1-phenylethyl)-1H-imidazole-5-carboxylate (FETO), ethyl 8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-benzo-[f]imidazo[1,5-a]-[1,4]diazepine-3-carboxylate (FMZ)/2-fluoroethyl 8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-benzo-[f]imidazo[1,5-a]-[1,4]diazepine-3-carboxylate (FFMZ), methyl 1-phenylethyl-4-(N-propanoylanilino)piperidine-4-carboxylate (CFN)/2-fluoroethyl 1-phenylethyl-4-(N-propanoylanilino)piperidine-4-carboxylate (FE@CFN) and methyl 2,4-diethyl-3-methylsulfanylcarbonyl-6-phenylpyridine-5-carboxylate [(Me)2@SUPPY]/2-fluorethyl 2,4-diethyl-3-ethylsulfanylcarbonyl-6-phenylpyridine-5-carboxylate (FE@SUPPY) under physiological conditions. The enzymatic reactions were stopped at different time points and analyzed by a standard protocol. Results: The Michaelis–Menten constants (K M) and limiting velocities (V max) are comparable. The statistical K M values were as follows: β-CIT/FE@CIT, P>.05; MTO/FETO, P>.06; ETO/FETO, P>.09; FMZ/FFMZ, P>.05; CFN/FE@CFN, P>.9; (Me)2@SUPPY/FE@SUPPY, P>.07. Conclusion: We found no statistical difference in stability against CES in vitro. These findings support the strategy to translate C-11-methyl-/ethylesters into their longer-lived F-18-fluoroethyl analogues. [ABSTRACT FROM AUTHOR]

Background. The aim of this pilot study was to assess tumour hypoxia in patients with cervical cancer before, during and after combined radio-chemotherapy and Magnetic Resonance Imaging (MRI) guided brachytherapy (BT) by use of the hypoxia Positron Emission Tomography (PET) tracer 18F-fluoroazomycin-arabinoside (18FAZA ). Material and methods. Fifteen consecutive patients with locally advanced cervical cancer referred for definitive radiotherapy (RT) were included in an approved clinical protocol. Stage distribution was 3 IB1, 1 IB2, 10 IIB, 1 IIIB, tumour volume was 55 cm3 (+/− 67, SD). Dynamic and static 18FAZA -PET scans were performed before, during and after external beam therapy (EBRT) and image guided BT +/− concomitant cisplatin. Dose was prescribed to the individual High Risk Clinical Target Volume (HR CTV) taking into account the dose volume constraints for adjacent organs at risk. Results. Five patients had visually identifiable tumours on 18FAZA -PET scans performed prior to radio-chemotherapy and four patients before brachytherapy. One of five 18FAZA PET positive patients had incomplete remission three months after RT, one had regional recurrence. Four of ten 18FAZA-PET negative patients developed distant metastases. The one patient with incomplete remission received 69 Gy (D90) in the HR CTV, whereas all other patients received mean 99 Gy (+/−12, SD). Conclusion. PET imaging with 18FAZA is feasible in patients with cancer of the uterine cervix. However, its predictive and prognostic value remains to be clarified. This applies in particular for the additional value of 18FAZA-PET compared to morphologic repetitive MRI within the setting of image guided high dose radiotherapy which may contribute to overcome hypoxia related radioresistance. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Recently, [18F]FE@SUPPY and [18F]FE@SUPPY:2 were introduced as the first positron emission tomography (PET) tracers for the adenosine A3 receptor. Thus, aim of the present study was the metabolic characterization of the two adenosine A3 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 [18F]FE@SUPPY was intact compared to 33.1% of [18F]FE@SUPPY:2; 30 min pi 30.3% intact [18F]FE@SUPPY was found compared to 15.6% [18F]FE@SUPPY:2. In brain, [18F]FE@SUPPY:2 formed an early hydrophilic metabolite, whereas metabolism of [18F]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 [18F]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 [18F]FE@SUPPY. [Copyright &y& Elsevier]

Abstract: 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. [Copyright &y& Elsevier]

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-HT1A) receptor. Sixteen healthy women and 16 healthy men were measured using PET and the highly specific radioligand [ carbonyl-11C]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-HT1A receptor BPND 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-HT1A receptor BPND was found equally distributed in men and women applying both the manual delineation method and the automated delineation approach. Women had lower mean BPND 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-HT1A receptor BPND 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-HT1A 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-HT1A receptor expression. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: Since the late 1980s, cocaine analogues based on the phenyltropane structure, such as [11C]CFT and [123I]β-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 β-CIT, FP-CIT and FE@CIT against carboxyl esterases and (2) evaluate selectivity of [18F]FE@CIT compared to [123I]β-CIT and [123I]FP-CIT using autoradiography. Methods: In vitro enzymatic hydrolysis assays were performed using different concentrations of β-CIT, FE@CIT and FP-CIT with constant concentrations of carboxyl esterase. Autoradiography was performed on coronal 20-μm rat brain sections incubated with different radioactivity concentrations of [123I]β-CIT, [123I]FP-CIT or [18F]FE@CIT and, additionally, with 3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile [serotonin transporter (SERT)] and nisoxetine [norepinephrine transporter (NET)] for blocking experiments. Results: In vitro assays showed Michaelis-Menten constants of 175 μmol (β-CIT), 183 μmol (FE@CIT) and 521 μmol (FP-CIT). Limiting velocities were 0.1005 μmol/min (β-CIT), 0.1418 μmol/min (FE@CIT) and 0.1308 μmol/min (FP-CIT). This indicates a significantly increased stability of FP-CIT, whereas carboxyl esterase stability of β-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 [18F]FE@CIT than for the other two tracers. Conclusion: We found that (1) the metabolic stability of FE@CIT was comparable to that of β-CIT, whereas FP-CIT showed higher resistance to enzymatic hydrolysis; and (2) the overall uptake pattern of [18F]FE@CIT on brain slices was comparable to that of [123I]β-CIT and [123I]FPCIT. After blocking of NET and SERT binding, a significantly higher DAT selectivity was observed for [18F]FE@CIT. Hence, [18F]FE@CIT may be of interest for further clinical application. [Copyright &y& Elsevier]

Abstract: Purpose: The present study aimed to develop convenient preparation and quality control protocols for [68Ga]-EDTMP, a potential radiotracer for skeletal PET imaging. Furthermore, bone binding characteristics with special focus on the influence of carrier addition were evaluated. Methods: No-carrier-added (nca), carrier-added and novel cross-complexed [68Ga]-EDTMP formulations were prepared using [68Ga]-gallium chloride and a commercial EDTMP kit. Respective bone binding characteristics were determined on the basis of an established in-vitro method using hydroxyapatite and human bone powders as binding matrices. Results: Pre-vivo evaluation of nca [68Ga]-EDTMP yielded irreversible binding on the mineral bone phase characterised by fast binding kinetics. Generally, nca [68Ga]-EDTMP showed low uptake values comparable to nca [99mTc]-EDTMP. Interestingly, the bone binding affinity of [68Ga]-EDTMP could be increased by the addition of carriers, presumably by changing the complex structure. Conclusions: This fast and reliable preparation protocol could enable small PET facilities without onsite cyclotron to perform PET bone scans. A comparison of all cross-complexed [68Ga]-EDTMP preparations further strengthens the recently presented “foreign carrier theory”, which highlights carrier addition as a factor strongly affecting bone uptake of radiolabelled polyphosphonates. The clinical applicability of [68Ga]-EDTMP – particularly with respect to lesion specificity and sensitivity – should be clarified in forthcoming in-vivo studies. [Copyright &y& Elsevier]

Abstract: Introduction: Changes of the adenosine A3 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 [18F]FE@SUPPY and a first evaluation of [18F]FE@SUPPY in rats. Methods: [18F]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 [18F]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 [18F]FE@SUPPY has the potential to serve as the first positron emission tomography tracer for the A3AR. [Copyright &y& Elsevier]

Abstract: Introduction: The translation of 11C-labeled compounds into their respective 18F-labeled derivatives is an important tool in the rapid development of positron emission tomography (PET) tracers. Thus, our aim was the development of a general method for the preparation of 18F-fluoroethylated compounds that (a) is applicable to a variety of precursors, (b) can be performed in a fully automated commercially available synthesizer and (c) enables this rapid translation of 11C-methylated tracers into their 18F-fluoroethylated analogs sharing the same precursor molecules. Methods: Ten methods for the preparation and purification of different 18F-fluoroethylating agents were compared. Subsequently, five 18F-labeled PET tracers were synthesized under fully automated conditions. Results: Radiochemical yields ranged from 34.4% to 60.8%, and time consumption ranged from 20 to 55 min for all methods. Use of 1-bromo-2-[18F]fluoroethane and distillation evinced as the method of choice. Conclusions: We were able to develop a general method for the preparation of a variety of 18F-fluoroethylated molecules. The provided tool is solely based on commercially available resources and has the potential to simplify and accelerate innovative PET tracer development in the future. [Copyright &y& Elsevier]

Purpose and Methods: 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-[11C]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-[11C]verapamil kinetics in homologous brain volumes of interest (VOIs) located ipsilateral and contralateral to the seizure focus. Results: 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 K1 and efflux rate constants k2 of R-[11C]verapamil were descriptively increased as compared to the contralateral side. Parameter asymmetries were most prominent in parahippocampal and ambient gyrus ( K1, range: −3.8% to +22.3%; k2, range: −2.3% to +43.9%), amygdala ( K1, range: −20.6% to +31.3%; k2, range: −18.0% to +38.9%), medial anterior temporal lobe ( K1, range: −8.3% to +14.5%; k2, range: −14.5% to +31.0%) and lateral anterior temporal lobe ( K1, range: −20.7% to +16.8%; k2, 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, K1, range: −3.7% to +4.5%; k2, range: −4.2% to +5.8%). In 5 of 7 patients, ipsilateral efflux ( k2) increases were more pronounced than ipsilateral influx ( K1) increases, which resulted in ipsilateral reductions (10%–26%) of R-[11C]verapamil distribution volumes (DV). However, for none of the examined brain regions, any of the differences in K1, k2 and DV between the epileptogenic and the nonepileptogenic hemisphere reached statistical significance (p > 0.05, Wilcoxon matched pairs test). Conclusions: Even though we failed to detect statistically significant differences in R-[11C]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. [ABSTRACT FROM AUTHOR]

Introduction: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. GIST has been shown to over-express c-KIT (CD117), the receptor tyrosine kinase. Imatinib (STI571 or Glivec) is a new type of tyrosine kinase inhibitor that selectively inhibits various tyrosine kinases and has been successfully used to treat GIST. In this study we have compared the results of F-18 FDG PET with those of CT in patients with GIST before and early after the treatment with Imatinib. Methods: The performance of CT and FDG PET imaging in the staging and follow-up of GIST lesion was retrospectively evaluated and compared in 15 patients with 67 suspicious lesions. All patients were examined before and after treatment with Imatinib. Findings of CT and FDG PET were compared on both patient- and lesion-based basis for the whole group and for anatomic locations. Results: Overall 67 lesions were detected in both pre-therapeutic FDG PET and CT imaging. In the pre-treatment studies there was no significant difference between detected lesions on FDG PET and CT (p = 0.19). However, after treatment with Imatinib (follow-up interval of 30 ± 16 days), FDG PET predicted response to therapy earlier than CT in 18% of lesions and 14% of patients, respectively. There was no significant difference in the density of malignant lesions by means of Hounsfield unit (HU) in the baseline PET in comparison to the early post-therapeutic investigations (93 ± 16 vs. 90 ± 22). Conclusion: For treatment monitoring of Imatinib in GIST patients, FDG PET gives more precise information of active state of disease compared with CT. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: The objectives of this study were to develop a simple preparation method for [68Ga]-EDTMP and to evaluate the applicability of [68Ga]-EDTMP as a potential positron emission tomography (PET) bone imaging agent using pre vivo, ex vivo and in vivo models. Methods: [68Ga]-EDTMP was prepared using [68Ga]-gallium chloride eluted from the 68Ge/68Ga generator and commercially available Multibone kits. Binding affinity to bone compartments was evaluated using a recently established pre vivo model. In vivo (microPET) and ex vivo experiments were performed in mice, and the results of which were compared with those obtained with [18F]-fluoride. Results: [68Ga]-EDTMP was accessible via simple kit preparation and predominantly accumulated in bone tissue in vivo, ex vivo and pre vivo. Binding to mineral bone was irreversible, and low binding was observed in organic bone. In vivo microPET evaluation revealed predominant uptake in bone with renal excretion. Compared with [18F]-fluoride, the uptake was lower and the PET image quality was reduced. Conclusions: From the present evaluation, apart from the autonomy for PET centers without an onsite cyclotron, the advantage of [68Ga]-EDTMP over [18F]-fluoride is not apparent and the future clinical prospect of [68Ga]-EDTMP remains speculative. [Copyright &y& Elsevier]

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

Abstract: We explored the relationship between striatal dopamine-2 (D2) receptor occupancy and extra-pyramidal symptoms (EPS) in bipolar patients receiving olanzapine. Seventeen patients with a DSM-IV diagnosis of bipolar disorder were treated with 5–45 mg/day olanzapine for at least 14 days. After that period, D2 receptor occupancy was determined using Iodobenzamide (IBZM) and SPECT. EPS were assessed by the Simpson–Angus Scale (SAS) and Barnes–Akathisia Scale (BAS). We found a dose-dependent increase in occupancy: 5 mg led to 28–50%, 10 mg to 40–68%, 15 mg to 69%, 20 mg to 57–66%, 30 mg to 66% and 45 mg to 80% D2 receptor occupancy; and a significant correlation between plasma levels and occupancy (R 2 =.55, P =.001). Similar to schizophrenic patients, bipolar patients did not exhibit EPS at D2 occupancy levels of 28 to 80%. Although we did not find an increased vulnerability for acute EPS in bipolar patients receiving olanzapine at clinical relevant doses, this needs to be replicated with larger sample sizes. [Copyright &y& Elsevier]

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 (67Ga) scintigraphy results with those obtained by positron emission tomography (PET) using 11C-acetate in patients with HCC. Methods: We prospectively analysed 21 patients (mean age, 64±11 years) with histopathologically verified HCC undergoing 11C-acetate PET and 67Ga scintigraphy. 67Ga scans were not performed in three of these 21 patients due to the exacerbation of the disease. Whole-body 11C-acetate PET were performed following intravenous injection of 850 MBq of 11C-acetate. For 67Ga scintigraphy, whole-body, planar and single photon emission computed tomography imaging acquisitions were performed after intravenous application of a mean dose of 189 MBq 67Ga. Results: 67Ga 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. 11C-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 67Ga scintigraphy nor the conventional computed tomography have shown the lesions, which were clearly demonstrated by the 11C-acetate PET. Conclusion: Our results indicate significantly higher sensitivity and specificity of 11C-acetate PET than 67Ga scan in detection of HCC lesions. This study suggests that imaging with 11C-acetate PET might play a potential role in the diagnostic workup of patients with HCC. [ABSTRACT FROM AUTHOR]

Aim Recombinant human thyrotropin (rhTSH) is a new option for diagnostic follow-up in patients with differentiated thyroid cancer (DTC). Iodine kinetics after administration of rhTSH is controversially discussed. The aim of our study was to compare the time course of radioiodine in tumour and normal tissue during periods of TSH elevation in patients in a hypothyroid state (HS) following hormone withdrawal, with those under euthyroidism (ES) after the administration of rhTSH. Patients and methods We investigated four patients who had undergone near-total thyroidectomy and were suffering from metastatic disease. Dosimetric calculations were performed using tumour and whole-body uptake, and background measurements from 123-iodine scans performed 0, 4, 24 and 48 h after the application of 123I. Results All patients had lesser uptake of 123I under rhTSH stimulation than after hormone withdrawal. The median maximum TG (thyroglobulin) levels were 733·1 ng/ml with HS and 548·0 ng/ml with ES. The median half-life in tumour tissue was 39·8 h (mean 65·9, range 11·5–194·0) with HS and 21·9 h (mean 38·7, range. 8·7–113·9) with ES. The median uptake dose in per cent in tumour tissue was 0·08 (mean 0·15, range 0·04–0·6) with HS and 0·05 (mean 0·08, range 0·03–0·2) with ES. Furthermore, the cumulative activity in metastatic tissue was lower after rhTSH than during hypothyroidism, with considerable variations between individual lesions. Conclusion In our small group of DTC patients with metastatic disease, the effectiveness of radioiodine therapy following rhTSH was anticipated to be less than that in individuals who were hypothyroid after levothyroxine (L-T4) withdrawal. Endogenous TSH stimulation of metastatic thyroid cancer with radioiodine should not be performed without prior target tumour lesion dosimetry with 123I. [ABSTRACT FROM AUTHOR]

Purpose: 11β-Hydroxylase is a key enzyme in the biosynthesis of adrenocortical steroid hormones and is a suitable target for the imaging of the adrenal cortex. [11C]Metomidate (MTO), [11C]etomidate (ETO) and desethyl-[18F]fluoroethyl-etomidate (FETO) are potent inhibitors of this enzyme and are used for PET imaging of adrenocortical pathologies. The aims of this study were (1) to evaluate and compare the metabolic stability of MTO, ETO and FETO against esterases and (2) to investigate the metabolic pattern of FETO in vivo. Methods: In vitro assays were performed using different concentrations of MTO, ETO and FETO with constant concentrations of carboxylesterase. Human in vivo studies were performed with human blood samples drawn from the cubital vein. After sample clean-up, the serum was analysed by HPLC methods. Results: In vitro assays showed Michaelis-Menten constants of 115.1 µmol for FETO, 162.0 µmol for MTO and 168.6 µmol for ETO. Limiting velocities were 1.54 µmol/min (FETO), 1.47 µmol/min (MTO) and 1.35 µmol/min (ETO). This implies insignificantly decreased esterase stability of FETO compared with MTO and ETO. In vivo investigations showed a rapid metabolisation of FETO within the first 10 min (2 min: 91.41%±6.44%, n=6; 10 min: 23.78%±5.54%, n=4) followed by a smooth decrease in FETO from 20 to 90 min (20 min: 11.23%±3.79% n=4; 90 min: 3.68%±3.65%, n=4). Recovery rate was 61.43% ±3.19% (n=12). Conclusion: In vitro experiments demonstrated that FETO stability against esterases is comparable to that of ETO and MTO. The metabolic profile showed that FETO kinetics in humans are fast. [ABSTRACT FROM AUTHOR]

Purpose: 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 11β-hydroxylase inhibitor, [18F] FETO, in rats displaying high tracer accumulation in the adrenals. In this study, we aimed to investigate for the first time the potency of [18F]FETO as a PET tracer for the adrenal cortex in humans. Methods: An average preparation yielded 1-2 GBq of [18F]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 [18F] 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. Results: [18F]FETO distribution was similar in all scanned volunteers. Visually, pronounced accumulation of [18F] 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). Conclusion: [18F]FETO is a valuable tracer for adrenocortical PET imaging, combining the longer half-life of 18F with a high 11β-hydroxylase selectivity. In accordance with our findings in rats, FETO PET revealed very high accumulation in the adrenal glands in healthy volunteers. [ABSTRACT FROM AUTHOR]

Purpose: Although polyphosphonates (PPs) were introduced as bone imaging agents in nuclear medicine in the early 1970s, the mechanisms involved in their uptake still remain unclear. Suggested mechanisms range from mineral adsorption with disputed binding to the organic phase, over incorporation into the mineralisation process to a combination of both mechanisms. Thus, our investigations aimed to: (1) evaluate adsorption parameters of 99mTc-MDP, 153Sm-EDTMP and 18F-fluoride on mineralising osteoblast cultures, (2) correlate the radiotracer binding measured in the cell cultures with binding values from our previously presented mineral model and (3) compare binding with cell number. Methods: Primary osteoblasts were obtained by sequential digestion of foetal mice calvariae. The cells were incubated with 0.3 µmol of radiolabelled PPs or 25 MBq 18F-fluoride for 120 min. Gamma signals from labelled samples were detected with a Millennium Hawkeye SPECT camera or with a dedicated Advance full-ring PET scanner and the binding percentages were calculated. Results: From days 8 to 15 of culture, the percent binding of all evaluated tracers increased significantly, whereas the protein concentration showed insignificant changes. Additional comparisons of the binding values with our recently published pre-vivo model revealed remarkable agreement, suggesting solely bone-forming minerals to be responsible for radiotracer binding. Conclusion: This study provides evidence that binding of the evaluated radiotracers is not associated with osteoblast numbers but only with the concentration of bone-forming minerals. The presented correlations substantiate our recently presented pre-vivo model for the evaluation of bone-seekers: mechanisms associated with the uptake of bone-seekers are irreversible and mineral-associated processes. [ABSTRACT FROM AUTHOR]

Abstract: Nucleophilic aromatic substitution is a challenging task in radiochemistry. Therefore, a thorough evaluation and optimisation of this step is needed to provide a satisfactory tool for the routine preparation of [18F]fluorinated aromatic amino acids. Two methods, already proposed elsewhere, were evaluated and improved. The yields for the radiofluorination were increased whereas activity loss during solid phase extraction was observed. Radiochemical yields for the two methods were 92.7±5.5% (method 1) and 92.1±12.3% (method 2) for conversion and 11.1±2.8% (method 1) and 34.8±0.6% (method 2) for purification, respectively. In total, we demonstrate an optimised method for the preparation of this important class of [18F]fluorinated synthons for PET. [Copyright &y& Elsevier]

Abstract: The present study focused on the preparation of novel bone tracers containing yttrium as radionuclide or carrier. Moreover, these preparations were comparatively evaluated in vitro on the basis of a recently presented pre vivo model comprising binding studies on synthetic and human bone powder. It was shown that among the therapeutic radionuclides, no carrier added [90Y]-EDTMP exceeded [188Re]-EDTMP while yielding lower binding values than [153Sm]-EDTMP. Furthermore, the authors investigated the influence of “foreign” carriers added to [90Y]-EDTMP, [99mTc]-EDTMP and [111In]-EDTMP by the method of cross-complexation. The findings reveal a new paradigm: a carrier more foreign to the complexed radionuclide causes a higher binding increase on human bone matrices in vitro than a more “related” carrier. [Copyright &y& Elsevier]

Purpose: Radioiodine-negative thyroid cancer presents diagnostic and therapeutic difficulties, warranting the implementation of new imaging and treatment strategies. The purpose of this study was twofold. First, we investigated in vitro the binding characteristics of 111In-DOTA-lanreotide (111In-DOTA-LAN) and 111In-DOTA-DPhe¹-Tyr³-octreotide (111In-DOTA-TOC) to cells derived from differentiated thyroid cancer (DTC). Second, we evaluated the value of somatostatin receptor (SSTR) scintigraphy with these radioligands, as compared with 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET), for the detection of tumour lesions in DTC patients. Methods: Binding of 111In-DOTA-LAN and 111In-DOTATOC to cells isolated from surgically removed thyroid tissue was evaluated in vitro by performing saturation and displacement studies. Eighteen DTC patients with elevated thyroglobulin (12 radioiodine-negative, six radioiodine-positive) were investigated with 111In-DOTA-LAN, 111In-DOTA-TOC and 18F-FDG PET scans. Results: Large numbers of SSTR binding sites for 111In-DOTA-LAN and 111In-DOTA-TOC were found on the cells investigated. Both SSTR radioligands exhibited a high binding affinity for these SSTR binding sites. 111In-DOTALAN and 111In-DOTA-TOC scintigraphy detected 37 and 33 lesions, respectively, in 17 (94%) patients each, whereas 18F-FDG PET revealed 30 lesions in 15 (83%) patients. Uptake of both SSTR radioligands was found in several radioiodine-negative sites. No striking differences in lesion imaging by 111In-DOTA-LAN and 111In-DOTA-TOC were found. In both radioiodine-negative and radioiodine-positive patients, more lesions were SSTR-positive/18F-FDG-negative than were 18F-FDG-positive/SSTR-negative. Conclusion: Adding a SSTR scan with these radioligands to the diagnostic work-up increases the diagnostic capacity in DTC, and should be considered particularly in radioiodine-negative patients with elevated thyroglobulin levels. [ABSTRACT FROM AUTHOR]

Abstract: Introduction : Although the first polyphosphonates (PP) were introduced to nuclear medicine as bone imagers in the early 70s, mechanisms involved in uptake still remain speculative. Controversies range from adsorption onto the mineral phase with disputed binding to the organic phase, over incorporation into the mineralisation process to a combination of both mechanisms. Other factors such as solubility of the complex, concentration of ligand or effects of the radionuclide have also been discussed as possible parameters influencing bone uptake. Therefore, the present work aimed to verify the recently presented pre vivo model which was developed to rate the influence of various factors on the binding of differently radiolabelled PP and [18F]-fluoride on synthetic bone matrix. Methods : Radiolabelled polyphosphonates and [18F]-fluoride were added to a vial containing lyophilised and milled spongiosa (Sp) or cortical bone (Co) in Hank''s Balanced Salt Solution. After incubation, the radioactivity was measured in the gamma-counter before and after filtration. The percentage of irreversibly bound radioactivity was calculated. Same experiments were performed after decalcification of Sp and Co with hydrochloric acid. Results : Descriptively, [111In] increases the uptake of EDTMP in each case compared to similarly prepared [99mTc]-analogues: [111In]-EDTMP > [99mTc]-EDTMP, [111In]-/In-EDTMP > [99mTc]-/In-EDTMP and [111In]-/Re-EDTMP > [99mTc]-/Re-EDTMP. [188Re]-EDTMP shows higher binding than the carrier-added analogue, contradicting recent in vivo findings of [188Re]-PP. However, our findings on human matrix are consistent with those of a previous study using artificial bone material. Binding on decalcified tissue was very low (PP) to moderate ([18F]-fluoride) and reversible. Remarkable is also the unrivalled high uptake of [18F]-fluoride, showing no reduced uptake on Co and Sp as compared to hydroxyapatite (HA) and amorphous calcium phosphate (ACP). Conclusion : The binding of the evaluated bone seekers on these human bone matrices follows a comparable pattern as on artificial bone. The present study substantiates the fact that binding predominantly occurs on the inorganic compartment of bone. The best correlation was found between HA and Co. Therefore, HA can serve as a matrix for representative binding studies. [Copyright &y& Elsevier]

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. 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). T cells from patients with a high TPOAb titre (group I) had significantly higher percentages of cells producing IFN-γ 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-γ 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-β. Similarly, patients in group I also showed higher percentages of TNF-α positive cells than healthy donors (group III). In this case, cells expressing TNF-α alone as well as cells coexpressing TNF-α and IFN-γ 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). 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. [ABSTRACT FROM AUTHOR]

Abstract: Aim:: In advanced seminoma the management of residuals after completion of chemotherapy is controversial. Some centres routinely perform surgery for lesions ≥3cm 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. Materials and methods:: 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 (< or ≥3cm) of the residual masses. Results:: Fifty-two PET scans were evaluable. After adequate chemotherapy, there were 74 CT-documented residual masses ranging in size from 1 to 11cm (median, 2.2cm). Their dignities were confirmed histologically in 13 lesions, or by follow-up CT in 61 lesions. Four of forty-seven lesions <3cm and 11/27 lesions ≥3cm were viable. PET was true positive in one lesion <3cm and in 11 lesions ≥3cm, false negative in three lesions <3cm, and true negative in 59 lesions (43 lesions <3cm). 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 (< or ≥3cm); and 80% (51–95), and 100% (93–100), respectively, for PET (specificity, P < 0.001). Conclusion:: 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 a ≥3cm cut-off. A negative PET scan is excellent for the exclusion of disease in lesions ≥3cm, 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 lesions ≥3cm. [Copyright &y& Elsevier]

Abstract: At present, most data available on PET imaging of brain tumors using amino acids are based on l-[S-methyl-11C]methionine (MET). This radiopharmaceutical accurately delineates tumor extent, sometimes even better than CT. Since MET is playing such an important role for PET, a potent preparation method for this radiotracer allowing frequent syntheses for PET routine is desirable. Therefore, a simple disposable synthesis module was conceived without HPLC purification. Using a solid supported [11C]methylation on Al2O3 leads to the simplification of the preparation requiring only filtration for separation of precursor and MET. The presented method is able to produce high purity MET in excellent yields enough to serve several consecutive patients. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

Purpose: 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. Methods: For the in vitro experiments, suspensions of various E. coli strains were incubated with different concentrations of [18F]ciprofloxacin (0.01-5.0 μg/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. Results: 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. Conclusion: Taken together, our results indicate that [18F]ciprofloxacin is not suited as a bacteria-specific infection imaging agent for PET. [ABSTRACT FROM AUTHOR]

Purpose. 11C-metomidate (MTO), a marker of 11β-hydroxylase, has been suggested as a novel positron emission tomography (PET) tracer for adrenocortical imaging. Up to now, experience with this very new tracer is limited. The aims of this study were (1) to evaluate this novel tracer, (2) to point out possible advantages in comparison with 18F-fluorodeoxyglucose (FDG) and (3) to investigate in vivo the expression of 11β-hydroxylase in patients with primary aldosteronism. Methods. Sixteen patients with adrenal masses were investigated using both MTO and FDG PET imaging. All patients except one were operated on. Five patients had non-functioning adrenal masses, while 11 had functioning tumours(Cushing’s syndrome, n=4; Conn’s syndrome, n=5; phaeochromocytoma, n=2). Thirteen patients had benign disease, whereas in three cases the adrenal mass was malignant (adrenocortical cancer, n=1; malignant phaeochromocytoma, n=1; adrenal metastasis of renal cancer, n=1). Results. MTO imaging clearly distinguished cortical from non-cortical adrenal masses (median standardised uptake values of 18.6 and 1.9, respectively, p<0.01). MTO uptake was slightly lower in patients with Cushing’s syndrome than in those with Conn’s syndrome, but the difference did not reach statistical significance. The expression of 11β-hydroxylase was not suppressed in the contralateral gland of patients with Conn’s syndrome, whereas in Cushing’s syndrome this was clearly the case. The single patient with adrenocortical carcinoma had MTO uptake in the lower range. Conclusion. MTO could not definitely distinguish between benign and malignant disease. FDG PET, however, identified clearly all three study patients with malignant adrenal lesions. We conclude: (1) MTO is an excellent imaging tool to distinguish adrenocortical and non-cortical lesions; (2) the in vivo expression of 11β-hydroxylase is lower in Cushing’s syndrome than in Conn’s syndrome, and there is no suppression of the contralateral gland in primary aldosteronism; (3) for the purpose of discriminating between benign and malignant lesions, FDG is the tracer of choice. [ABSTRACT FROM AUTHOR]

Detection and follow up of bone metastases are important in diagnostic nuclear medicine. However, although the methods are well established, the mechanisms involved in the bone uptake of radiotracers still remain speculative. The aim of the present study was the evaluation and comparison of the labelling of EDTMP with different radionuclides (n.c.a.=no carrier added) and different carriers (c.a.=carrier added). Since different nuclides have an impact on the radiochemical and biological properties of the tracer, our experiments were designed to further elucidate the mechanisms and structural prerequisites for bone uptake.We labelled the commercially available Multibone® kit with [111In] and [99mTc] using different carriers, e.g. indium and rhenium, to form “cross complexes”. In the case of [188Re] we compiled minor modifications to this kit for the first time allowing the simple preparation of [188Re]-EDTMP in the departments without on-site radiopharmacy. [Copyright &y& Elsevier]

Introduction. Although the first polyphosphonates were already introduced in the early 1970s, mechanisms involved in uptake still remain speculative. The present work aimed to establish a new method to rate the influence of various factors on the uptake and to evaluate new bone-seekers on these bone compartments. Methods. Radioactive-labelled diphosphonates and [18F]-fluoride were added to a vial containing hydroxyapatite (HA), collagen, or amorphous calcium phosphate (ACP) in 3 ml of Hanks'' Balanced Salt Solution (HBSS). After incubation, these suspensions were filtered, the radioactivity was measured in the gamma-counter, and the percentage of irreversibly bound radioactivity was calculated. Results. Kinetic experiments revealed uptake increase over time for [99mTc]-MDP and [18F]-fluoride on various amounts of matrix. After 120 min, static studies on HA yielded: [99mTc]-EDTMP < [188Re]-/Re-EDTMP < [99mTc]-/11 μl Re-EDTMP < [99mTc]-/In-EDTMP < [99mTc]-/15 μl Re-EDTMP < nca [188Re]-EDTMP < [111In]-/Re-EDTMP < [111In]-EDTMP < [111In]-/In-EDTMP < [99mTc]-DPD < [99mTc]-/80 μl Re-EDTMP < [99mTc]-EDTMP “boiled” < [99mTc]-/150 μl Re-EDTMP < [153Sm]-EDTMP < [99mTc]-/11 μl Re-EDTMP “boiled” < [18F]-ions < [99mTc]-MDP. Collagen showed very low uptake. Reincubation experiments suggest that bone tracers are irreversibly bound. Conclusion. The presented method is rapid and feasible to examine the adsorption of radioactive-labelled substances on bone components. Correlations between our findings and published in vivo data support the application as a simple model. [Copyright &y& Elsevier]

[11C]Flumazenil, a highly selective benzodiazepine antagonist is the most extensively used GABAA ligand for PET so far. To overcome half life disadvantages of 11C a [18F]-labeled flumazenil derivative, 2′-[18F]fluoroflumazenil (FFMZ) was developed and biologically evaluated with respect to the GABAA 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 [3H]flumazenil binding from membrane GABAA receptors with an IC50value (3.5 nM) comparable to that of Flumazenil (2.8 nM). The presented data confirm the potential of [18F]FFMZ for PET imaging of the GABA-ergic system. [Copyright &y& Elsevier]

Visualization and biopsy of sentinel lymph nodes play an important role in planning and controlling the therapy of breast cancer. Hitherto two methods—scintigraphy or gamma probe detection after injection of [99mTc]-nanocolloids and visual detection after injection of patent blue dye—are used routinely. There are no conclusive publications elucidating such important parameters as injection site, injection method and colloidal parameters. The present work aims to label Nanocoll® with [111In] to provide an alternative method, a simultanous one-compound dual-isotope application.Methods: [111In]-Indiumchloride was buffered with acetate and transferred to the nanocolloid. The colloid labelling reaction was complete after 30 min and filtrated through 100 nm Nuclepore® filters.Results: Incorporation yield of [111In]-Indium into the nanocolloid was nearly quantitative, the step associated with the major loss of activity was the particle sizing with a mean yield of 55%.Conclusion: The presented method allows for the routine supply of [111In]-nanocolloids. Size-filtered [111In]-Nanocoll® shows the same particle size range as [99mTc]-Nanocoll®. [Copyright &y& Elsevier]

Hashimoto's encephalitis is a term which describes encephalopathy associated with autoimmune thyroiditis, but it is not based on evidence, whether Hashimoto's encephalitis is a distinct clinical entity by itself. In previously reported cases of Hashimoto's encephalitis, abnormal brain perfusion studies have been reported. The aim of this study was to evaluate the prevalence of brain perfusion abnormalities in euthyroid patients with autoimmune thyroiditis. 99mTc Ethyl cystein dimer (ECD) single photon emission computed tomography (SPECT) studies were performed in a study group of 41 euthyroid patients with autoimmune thyroiditis and a matched control group of 35 healthy individuals. All study participants had a normal neurological investigation and a detailed neurological history taking. Individuals with known or suspected morphological brain abnormalities were excluded from the study. Zung's Self-Rating Anxiety Scale (SAS) and Zung's Self-Rating Depression Scale (SDS) were used to detect depression and mood disorders. Automatic quantification of perfusion was performed with both a voxel-based analysis as well as a volume-of-interest (VOI) based analysis of 46 predefined cortical and subcortical regions. The findings from both groups were compared to a reference template. In the voxel-based analysis, there was a significant difference between patients and controls in the mean volume of perfusion defects deviating 2SD below the normal values (21·8 ml vs. 10·4 ml; P = 0·02). Hyperperfused areas, however, did not differ significantly between study patients and controls. A significant correlation of the perfusion defects with time since diagnosis of autoimmune thyroiditis was seen ( r = 0·42). In the VOI-based analysis, abnormal regions were more frequent in the study group when compared to controls ( P < 0·01) However, no topographic pattern was apparent. Regarding neurological findings, no significant difference was found between study patients and controls. However, both the SAS and SDS scores differed significantly between the two groups, but there was neither a correlation between the two scores and perfusion abnormalities nor an association with depression in our study group. These findings of impaired brain perfusion in patients with autoimmune thyroiditis further strengthen the hypothesis of a possible cerebral involvement in autoimmune thyroiditis in individual cases. The presence of cerebral hypoperfusion suggests a cerebral vasculitis as the most likely pathogenetic model. [ABSTRACT FROM AUTHOR]

11β-Hydroxylase (CYP11B1, P450[sub11β]) plays an important role in the biosynthesis of cortisol and aldosterone and has been shown to be a good target for the in vivo imaging of adrenocortical incidentalomas in nuclear medicine. [[sup11]C]Metomidate (MTO), a potent inhibitor of this enzyme, is used for positron emission tomography (PET) imaging of adrenocortical pathology. The synthesis of (R)-1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid 2-[[sup18]F]fluoroethylester (FETO), a close analogue to MTO and etomidate (ETO), has been presented recently, and the present investigation aimed to characterise the in vivo distribution of FETO. Since ETO is a well-known anaesthetic drug acting via the GABAergic system, the interaction of FETO with GABA[subA] receptors was also evaluated. Eighteen male Sprague-Dawley rats were injected with 1.73–3.06 MBq of FETO into a tail vein after venodilatation in a 40°C water bath. Rats were sacrificed by exsanguination from the abdominal aorta under deep ether anaesthesia after 10 (n=6), 30 (n=6) or 60 min (n=6); organs were removed, weighed and counted. For binding experiments, rat cerebellar membranes were incubated for 90 min at 4°C in TC-50 buffer, 150 mM NaCl and 2 nM of [³H]flunitrazepam in the absence or presence of 10 μM diazepam or various concentrations of ETO, MTO and FETO. In vivo evaluation evinced very high uptake in the adrenal glands (7.52%±1.19% ID/g at 30 min), followed by lung (1.18%±0.19% ID/g, 10 min), liver (0.59%±0.13% ID/g, 10 min) and duodenum (0.7%±0.29% ID/g, 60 min). No defluorination nor fluoroethyl-ester cleavage was observed. When brain re- gions were compared with the thalamus (the reference region), highest relative uptake was seen in the cortex (2.34), followed by “ rest brain” (2.13) and cerebellum (1.96). FETO and ETO were able to increase the binding of [³H]flunitrazepam with similar potencies and to a comparable extent. It is concluded that FETO shows characteristics suitable for the imaging of adrenocortical pathology with PET. Binding experiments on GABA receptors demonstrate a comparable effect of FETO and ETO. Hence, FETO possibly could also be used to elucidate the function, dynamics and kinetics of narcotic drugs with PET. [ABSTRACT FROM AUTHOR]

PET with (R)-[O-methyl-11C] metomidate ([11C] MTO) is an attractive method for the characterisation of adrenal masses discriminating lesions of adrenal cortical origin from noncortical lesions. [11C] MTO was prepared by the reaction of [11C] methyliodide with the corresponding free acid. Three purification methods have been compared. The method of choice uses preparative HPLC with a ready-to-use weak acidic solvent. [Copyright &y& Elsevier]

Somatostatin receptor (SSTR) scintigraphy and gallium-67 citrate ([sup 67]Ga) scintigraphy have been used for visualisation of Hodgkin's lymphoma and non-Hodgkin's lymphoma. However, experience with B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT) type is very limited. The aim of this study was to prospectively compare the [sup 67]Ga scintigraphy results with those obtained by [sup 111]In-DOTA-dPhe[sup 1]-Tyr[sup 3]-octreotide ([sup 111]In-DOTA-TOCT) and [sup 111]In-DOTA-lanreotide ([sup 111]In-DOTA-LAN) scintigraphy in patients with proven MALT-type lymphoma. Comparative scintigraphic examinations using [sup 67]Ga, [sup 111]In-DOTA-TOCT and [sup 111]In-DOTA-LAN were performed in 18 patients (11 female and 7 male, median age 64±15 years) with histologically verified MALT-type lymphomas of various origin. Planar and single-photon emission tomography imaging acquisitions were performed after injection of a mean dose of 185±26 MBq [sup 67]Ga and 165±20 MBq [sup 111]In-DOTA-TOCT or [sup 111]In-DOTA-LAN. All scintigraphic results were correlated with other conventional examinations including gastroscopy, colonoscopy, endosonoscopy, ophthalmologic investigation, CT of the thorax and abdomen and bone marrow biopsy. This comparative study showed that [sup 67]Ga scintigraphy found abnormalities in 10 of 16 patients (63%) and detected 18 of 31 clinically involved sites (58%), but was false positive in three patients. [sup 111]In-DOTA-TOCT found abnormalities in 9 of 15 patients (60%) and detected 15 of 27 clinical lesions (56%); it was false positive in two patients. [sup 111]In-DOTA-LAN scintigraphy showed abnormalities in 7 of 11 patients (64%) and found 12 of 22 clinical lesions (55%). False-positive [sup 111]In-DOTA-LAN scan results were found in two patients. For supra-diaphragmatic lesions, [sup 67]Ga scintigraphy detected 12 of 16 sites (75%). [sup 111]In-DOTA-TOCT scintigraphy revealed 7 of 15 lesions (47%). [sup 111]In-DOTA-LAN showed 6 of 12 positive sites (50%). For infra-diaphragmatic involvement, the sensitivities of [sup 67]Ga, [sup 111]In-DOTA-TOCT and [sup 111]In-DOTA-LAN were 40%, 67% and 60%, respectively. It is concluded that MALT-type lymphoma can be visualised by [sup 67]Ga, [sup 111]In-DOTA-TOCT and [sup 111]In-DOTA-LAN scintigraphy. Although there were no statistically significant differences in patient-related and site-related sensitivities when using [sup 67]Ga compared with [sup 111]In-DOTA-TOCT and [sup 111]In-DOTA-LAN, the sensitivity of [sup 67]Ga tended to be superior to that of [sup 111]In-DOTA-TOCT and [sup 111]In-DOTA-LAN for supra-diaphragmatic lesions but inferior for infra-diaphragmatic involvement. In selected cases, the combination of [sup 67]Ga and [sup 111]In-DOTA-LAN or [sup 111]In-DOTA-TOCT may increase the diagnostic efficiency in patients with MALT-type lymphoma. [ABSTRACT FROM AUTHOR]

Impairment of the lacrimal glands after external radiation has been well documented, but there are only a few reports on the effects of radioiodine therapy on the lacrimal glands. Long-term effects of high-dose radioiodine therapy on tear secretion have not previously been studied. We investigated 175 eyes of 88 patients with a history of radioiodine therapy for thyroid carcinoma (68 females, 20 males; mean age 55±16 years, range 17–81 years) and compared them with a sex- and age-matched control group (n=39). All patients had been given at least 2.96 GBq iodine-131 (maximal administered activity 22.3 GBq [sup 131] I). An ophthalmological investigation was performed 64±71 months (range 3–317 months) after initial radioiodine therapy by a single ophthalmologist. Lacrimal gland function was evaluated with three different function tests. External eye morphology was considered, and detailed ophthalmological history-taking was performed. Patients with factors known to affect lacrimal gland function (contact lenses, autoimmune disorders, history of additional radiation exposure) were excluded from the study. A total of 81 patients (92%) had at least one abnormal function test indicating impaired lacrimal gland function. Schirmer's tear test was decreased (<10 mm/5 min) in 47 of the 88 patients and definitely abnormal (<5 mm/5 min) in 35 patients. A tear film break-up time of <10 s was found in 78 patients, and 62 patients had a definitely abnormal break-up time of <5 s. The lacrimal lipid layer was impaired in 43 patients. The function tests were all significantly altered in the study group as compared with the controls (P<0.005, P<0.001, P<0.001, respectively). Both subjective symptoms of dry eye (P<0.01) and changes in the external eye morphology (P<0.001) were significantly more prevalent in the study group. Our findings suggest that in the majority of patients, lacrimal gland function may be permanently impaired after high-dose radioiodine... [ABSTRACT FROM AUTHOR]