Peptide receptor radionuclide therapy of neuroendocrine tumors with (90)Y-DOTATOC: is treatment response predictable by pre-therapeutic uptake of (68)Ga-DOTATOC?

PURPOSE: PET with (68)Ga-DOTATOC allows for imaging and quantitative assessment of somatostatin receptor expression in neuroendocrine tumors (NET). The aim of this retrospective study was to analyze whether pre-therapeutic (68)Ga-DOTATOC PET/CT is able to predict response to Peptide Receptor Radionuclide Therapy (PRRT). PATIENTS AND METHODS: Forty patients with advanced stage NET were treated with a fixed dose of (90)Y-DOTATOC (5550 or 3700MBq). Prior to PRRT, each patient received (68)Ga-DOTATOC PET/CT. Treatment results were evaluated after 3months by CT, tumor marker levels and clinical course and correlated with (68)Ga-DOTATOC uptake (SUVmax) and the assumed uptake of (90)Y-DOTATOC in tumor manifestations (MBq/g). ROC analysis and pairwise comparison of area under the curve (AUC) were performed with pre-treatment uptake of (68)Ga-DOTATOC, assumed uptake of (90)Y-DOTATOC and treatment activity alone and in relation to body weight as continuous variables, and response/no response as classification variable. RESULTS: According to conventional criteria (tumor shrinkage, decrease of tumor markers, improved or stable clinical condition), 20 patients were classified as responders, 16 as non-responders and in four patients findings were equivocal. Using a SUV more than 17.9 as cut-off for favorable outcome, PET was able to predict treatment response of all responders and 15 out of 16 non-responders. All four patients with equivocal findings showed SUV less than or equal to 17.9 and soon experienced tumor progression. The assumed uptake of (90)Y-DOTATOC in tumor manifestations using a cut-off more than 1.26MBq/g as predictor of response was able to correctly classify 19 out of 20 responders, and 14 out of 16 non-responders. In all patients with equivocal findings, the assumed uptake of (90)Y-DOTATOC was below 1.26MBq/g. CONCLUSION: Pre-therapeutic (68)Ga-DOTATOC tumor uptake as well as assumed uptake of (90)Y-DOTATOC are strongly associated with the results of subsequent PRRT. The defined cut-off values should be confirmed by prospective studies and may then provide the rationale for individual dosing and selecting patients with high likelihood of favorable treatment outcome.

Comparison of particulate number concentrations in three Central European capital cities.

Number size distributions of atmospheric aerosol particles in the mobility diameter range from 10 to 1000 nm were determined in Budapest, Prague and Vienna for a one-year-long period. Particle number concentrations in various size fractions, their diurnal and seasonal variations, mean size distributions and some properties of new particle formation events were derived and compared. Yearly median particle number concentrations for Budapest, Prague and Vienna were 10.6×10(3), 7.3×10(3) and 8.0×10(3) cm(-3). Differences were linked to the different pollution levels of the cities, and to diverse measurement environments and local conditions. Mean contributions of ultrafine particles (particles with a mobility diameter <100 nm) to the total number concentration were 80%, 84% and 74% for Budapest, Prague and Vienna, thus these particles represent an overwhelming share of all particles in each city. Seasonal variation of particle number concentrations was not obvious. Diurnal variations of particles with a diameter between 100 and 1000 nm (N(100-1000)) exhibited similar shape for the cities, which was related to the time-activity pattern of inhabitants and regional influences. The structure of the diurnal variation for ultrafine particles was also similar. It contained a huge morning peak in each city which was explained by emissions from vehicular traffic. The second peak was shifted from afternoon rush hours to late evenings as a result of the daily cycling in meteorological parameters. The character of the measurement site also influenced the diurnal variation. Diurnal variation of the mean ratio of ultrafine particles to N(100-1000) clearly revealed the presence and importance of new particle formation and subsequent growth in urban environments. Nucleation frequencies in Budapest and Prague were 27% and 23%, respectively on a yearly time scale. They showed a minimum in winter for both places, while the largest nucleation activity was observed in spring for Budapest, and in summer for Prague.

[Application of MR/PET in oncologic imaging]. / Einsatz von MR/PET in der onkologischen Bildgebung.

The present review aims to depict the possibilities offered by hybrid imaging with magnetic resonance positron emission tomography (MR/PET). Recently, new whole-body MR/PET scanners were introduced allowing for the combination of both modalities outside the brain. This is a challenge for both modalities: For MRI, it is essential to provide anatomical images with high resolution. Additionally, diffusion-weighted imaging (DWI), proton spectroscopy, but also dynamic contrast-enhanced imaging plays an important role. With regard to PET, the technical challenge mainly consists of obtaining an appropriate MR-based attenuation correction for the PET data. Using MR/PET, it is possible to acquire morphological and functional data in one examination. In particular, children and young adults will benefit from this new hybrid technique, especially in oncologic imaging with multiple follow-up examinations. However, it is expected that PET/CT will not be replaced completely by MR/PET because PET/CT is less cost-intensive and more widely available. Moreover, in lung imaging, MRI limitations still have to be accepted. Concerning research, simultaneous MR/PET offers a variety of new possibilities, for example cardiac imaging, functional brain studies or the evaluation of new tracers in correlation with specific MR techniques.

Long-term study of cloud condensation nuclei (CCN) activation of the atmospheric aerosol in Vienna.

During a total of 11 months, cloud condensation nuclei (CCN at super-saturation S 0.5%) and condensation nuclei (CN) concentrations were measured in the urban background aerosol of Vienna, Austria. For several months, number size distributions between 13.22 nm and 929 nm were also measured with a scanning mobility particle spectrometer (SMPS). Activation ratios (i.e. CCN/CN ratios) were calculated and apparent activation diameters obtained by integrating the SMPS size distributions. Variations in all CCN parameters (concentration, activation ratio, apparent activation diameter) are quite large on timescales of days to weeks. Passages of fronts influenced CCN parameters. Concentrations decreased with the passage of a front. No significant differences were found for fronts from different sectors (for Vienna mainly north to west and south to east). CCN concentrations at 0.5% S ranged from 160 cm(-3) to 3600 cm(-3) with a campaign average of 820 cm(-3). Activation ratios were quite low (0.02-0.47, average: 0.13) and comparable to activation ratios found in other polluted regions (e.g. Cubison et al., 2008). Apparent activation diameters were found to be much larger (campaign average: 169 nm, range: (69-370) nm) than activation diameters for single-salt particles (around 50 nm depending on the salt). Contrary to CN concentrations, which are influenced by source patterns, CCN concentrations did not exhibit distinct diurnal patterns. Activation ratios showed diurnal variations counter-current to the variations of CN concentrations.

How the serotonin transporter 5-HTTLPR polymorphism influences amygdala function: the roles of in vivo serotonin transporter expression and amygdala structure.

The serotonin transporter-linked promoter region (5-HTTLPR) polymorphism of the serotonin transporter gene is associated with amygdala response during negative emotion. The aim of this study was to investigate whether this genotype effect on amygdala function is mediated by current serotonin transporter (5-HTT) levels or rather by genetically induced influences during neurodevelopment, shaping brain structure. A total of 54 healthy subjects underwent functional and structural magnetic resonance imaging, [(11)C]DASB positron emission tomography and 5-HTTLPR genotyping to analyze the interrelationships between amygdala activation during processing of unpleasant stimuli, 5-HTTLPR genotype, amygdala volumes and 5-HTT levels in the midbrain and in other brain regions. In line with previous research, carriers of the short allele (S) showed increased amygdala activation. Path analysis demonstrated that this genotype effect was not procured by current 5-HTT availability but by amygdala structure, with smaller amygdala volumes in the S than in the LL genotype, as well as smaller volumes being associated with increased amygdala activation. Our findings stress the role of genetic effects during neurodevelopment.

Characterizing the performance of two optical particle counters (Grimm OPC1.108 and OPC1.109) under urban aerosol conditions.

The performance of Grimm optical particle counters (OPC, models 1.108 and 1.109) was characterized under urban aerosol conditions. Number concentrations were well correlated. The different lower cut-off diameters (0.25 and 0.3 µm) give an average difference of 23.5%. Both detect less than 10% of the total particle concentration (0.01-1 µm; Differential Mobility Analyzer), but in the respective size ranges, differences are <10%. OPC number size distributions were converted to mass concentrations using instrument-specific factors given by the manufacturer. Mass concentrations for OPC1.108 were 60% higher than for OPC1.109 and (in case of OPC1.109) much lower than those measured with an impactor in the relevant size range or a TSP filter. Using the C-factor correction suggested by the manufacturer, OPC1.109 underestimated mass concentrations by 21% (impactor) and by about 36% (TSP filter), which is in the range of comparability of co-located different mass concentration methods (Hitzenberger, Berner, Maenhaut, Cafmeyer, Schwarz, & Mueller et al., 2004).

Automated synthesis of n.c.a. [18F]FDOPA via nucleophilic aromatic substitution with [18F]fluoride.

An improved, automated synthesis of [(18)F]FDOPA including four synthetic steps (fluorination, reductive iodination, alkylation and hydrolysis) is reported with each step optimized individually. In a home-made automatic synthesizer, 9064+/-3076 MBq of [(18)F]FDOPA were produced within 120 min from EOB (n=5). Radiochemical purity and enantiomeric excess were both >or= 95%. Specific activity was ca. 50 GBq/micromol at EOS. This automatically operable synthesis is well suited for the multi-patient-dose routine production of n.c.a. [(18)F]FDOPA.

Anxiety is associated with reduced central serotonin transporter availability in unmedicated patients with unipolar major depression: a [11C]DASB PET study.

Serotonergic dysfunction may contribute to negative mood states in affective disorders. Some in vivo imaging studies showed reduced availability of serotonin transporters (5-HTT) in the brainstem and thalamus of patients with major depression. We tested the hypothesis that 5-HTT availability is reduced in unmedicated unipolar patients with major depression compared to healthy control subjects matched for gender, age, genotype and smoking status. Availability of 5-HTT was measured in vivo with positron emission tomography and [(11)C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile (DASB) in the midbrain, thalamus and amygdala. DASB binding was correlated with the severity of depression (Beck's Depression Inventory), anxiety (Spielberger's State-Trait Anxiety Inventory) and personality traits (Temperament and Character Inventory). Patients with major depression displayed reduced 5-HTT availability in the thalamus (P=0.005). In patients, low serotonin transporter availability correlated with high anxiety (thalamus: r=-0.78, P=0.004; midbrain: r=-0.78, P=0.004; amygdala: r=-0.80, P=0.003). Correlations with severity of depression were weaker and did not survive correction for multiple testing. These results support the hypothesis that central serotonergic dysfunction is associated with negative mood states in affective disorders. In the thalamus, a low serotonin reuptake capacity may interfere with thalamic control of cortical excitability and contribute to anxiety rather than depression per se in major depression.

Reduced availability of serotonin transporters in obsessive-compulsive disorder correlates with symptom severity - a [11C]DASB PET study.

Reduced availability of brainstem serotonin transporters (5-HTT) has been observed in vivo in obsessive-compulsive disorder (OCD). However, results vary and may be influenced by competition with endogenous serotonin. Using positron emission tomography (PET) and [11C]DASB, a specific 5-HTT ligand that showed no competition with serotonin for 5-HTT binding in vitro, we tested the hypothesis that 5-HTT availability is reduced in OCD patients and correlated with OCD severity. METHODS. 5-HTT availability in the thalamus and the midbrain was measured in nine drug-free OCD patients and compared with 19 healthy controls, matched for the individual combination of 5-HTT genotype, gender and smoking status. OCD severity was assessed with the Yale-Brown obsessive compulsive scale (Y-BOCS). RESULTS. 5-HTT availability was significantly reduced in the thalamus and midbrain of OCD patients. Age and 5-HTT in the thalamus explained 83% of OCD severity in patients that were drug-free for at least 1 year. CONCLUSION. This PET study confirms a central role of the serotonergic system, particularly the thalamus in the pathogenesis of obsessive compulsive disorder.

Tumour hypoxia imaging with [18F]FAZA PET in head and neck cancer patients: a pilot study.

PURPOSE: Hypoxia is an important negative prognostic factor for radiation treatment of head and neck cancer. This study was performed to evaluate the feasibility of use of (18)F-labelled fluoroazomycin arabinoside ([(18)F]FAZA) for clinical PET imaging of tumour hypoxia. METHODS: Eleven patients (age 59.6 +/- 9 years) with untreated advanced head and neck cancer were included. After injection of approximately 300 MBq of [(18)F]FAZA, a dynamic sequence up to 60 min was acquired on an ECAT HR+ PET scanner. In addition, approximately 2 and 4 h p.i., static whole-body PET (n = 5) or PET/CT (n = 6) imaging was performed. PET data were reconstructed iteratively (OSEM) and fused with CT images (either an external CT or the CT of integrated PET/CT). Standardised uptake values (SUVs) and tumour-to-muscle (T/M) ratios were calculated in tumour and normal tissues. Also, the tumour volume displaying a T/M ratio >1.5 was determined. RESULTS: Within the first 60 min of the dynamic sequence, the T/M ratio generally decreased, while generally increasing at later time points. At 2 h p.i., the tumour SUV(max) and SUV(mean) were found to be 2.3 +/- 0.5 (range 1.5-3.4) and 1.4 +/- 0.3 (range 1.0-2.1), respectively. The mean T/M ratio at 2 h p.i. was 2.0 +/- 0.3 (range 1.6-2.4). The tumour volume displaying a T/M ratio above 1.5 was highly variable. At 2 h p.i., [(18)F]FAZA organ distribution was determined as follows: kidney > gallbladder > liver > tumour > muscle > bone > brain > lung. CONCLUSION: [(18)F]FAZA PET imaging appears feasible in head and neck cancer patients, and the achieved image quality is adequate for clinical purposes. Based on our initial results, [(18)F]FAZA warrants further evaluation as a hypoxia PET tracer for imaging of cancer.

Midbrain serotonin transporter binding potential measured with [11C]DASB is affected by serotonin transporter genotype.

BACKGROUND: Homozygote carriers of two long (L) alleles of the serotonin transporter (5-HTT) regulatory region displayed in vitro a twofold increase in 5-HTT expression compared with carriers of one or two short (S) alleles. However, in vivo imaging studies yielded contradictory results. Recently, an A > G exchange leading to differential transcriptional activation of 5-HTT mRNA in lymphobalstoid cell lines was discovered in the 5-HTT regulatory region. In vitro and in vivo evidence suggests that [(11)C]DASB, a new 5-HTT ligand offers some advantages over the ligands used in previous studies in measuring 5-HTT density independent of synaptic levels of serotonin. METHOD: We assessed 5-HTT binding potential (BP (2)) in the midbrain of 19 healthy subjects with positron emission tomography and [(11)C]DASB. Accounting for the hypothesized functional similarity of L (G) and S in driving 5-HTT transcription, we assessed whether L (A) L (A) homozygotes display increased midbrain BP (2) compared with carriers of at least one S allele. RESULTS: BP (2) in the midbrain was significantly increased in L (A) L (A) homozygotes compared with carriers of at least one S allele. Interestingly, the genotype effect on the midbrain was significantly different from that on the thalamus and the amygdala where no group differences were detected. CONCLUSIONS: This in vivo study provides further evidence that subjects homozygous for the L (A) allele display increased expression of 5-HTT in the midbrain, the origin of central serotonergic projections.

Moderate therapeutic efficacy of positron emission tomography-navigated repetitive transcranial magnetic stimulation for chronic tinnitus: a randomised, controlled pilot study.

BACKGROUND: Tinnitus has been shown to respond to modulations of cortical activity by high-frequency and low-frequency repetitive transcranial magnetic stimulation (rTMS). OBJECTIVE: To determine the tinnitus-attenuating effects of a 2-week daily regimen of rTMS, navigated to the maximum of tinnitus-related increase in regional cerebral blood flow. METHODS: Six patients with chronic tinnitus were enrolled in this sham-controlled crossover study and treated with 2x2 weeks of suprathreshold 1 Hz rTMS (30 min) applied to the region with maximal tinnitus-related increase in regional cerebral blood flow delineated by functional imaging with [15O]H2O positron emission tomography and a control area. Tinnitus-related distress was assessed before and after each treatment and 2 weeks after the end of the 4-week course of stimulation using a validated tinnitus questionnaire. Additional self-assessment scores of tinnitus change, loudness and annoyance were obtained. RESULTS: In five of six patients, rTMS induced greater reduction of the tinnitus questionnaire score than sham stimulation. In two patients, all parameters measured (tinnitus change score, tinnitus loudness, tinnitus annoyance) showed unequivocal improvement. At the group level, the degree of response in the tinnitus questionnaire score was correlated with tinnitus-associated activation of the anterior cingulate cortex. Two weeks after the final stimulation, tinnitus had returned to baseline in all patients but one. CONCLUSION: Tinnitus can be attenuated by low-frequency rTMS navigated to each person's maximum tinnitus-related cortical hyperactivity. The effects are only moderate; interindividual responsiveness varies and the attenuation seems to wear off within 2 weeks after the last stimulation session. Notably, tinnitus-related anterior cingulate cortex activation seems to predict the response to rTMS treatment.

CCN activation of pure and coated carbon black particles.

The CCN (cloud condensation nucleus) activation of pure and coated carbon black particles was investigated using the University of Vienna cloud condensation nuclei counter (Giebl, H.; Berner, A.; Reischl, G.; Puxbaum, H.; Kasper-Giebl, A.; Hitzenberger, R. J. Aerosol Sci. 2002, 33, 1623-1634). The particles were produced by nebulizing an aqueous suspension of carbon black in a Collison atomizer. The activation of pure carbon black particles was found to require higher supersaturations than predicted by calculations representing the particles as insoluble, wettable spheres with mobility equivalent diameter. To test whether this effect is an artifact due to heating of the light-absorbing carbon black particles in the laser beam, experiments at different laser powers were conducted. No systematic dependence of the activation of pure carbon black particles on laser power was observed. The observations could be modeled using spherical particles and an effective contact angle of 4-6 degrees of water at their surface. The addition of a small amount of NaCl to the carbon black particles (by adding 5% by mass NaCl to the carbon black suspension) greatly enhanced their CCN efficiency. The measured CCN efficiencies were consistent with Kohler theory for particles consisting of insoluble and hygroscopic material. However, coating the carbon black particles with hexadecanol (a typical film-forming compound with one hydrophobic and one hydrophilic end) efficiently suppressed the CCN activation of the carbon black particles.

[(11)C]d-threo-methylphenidate PET in patients with Parkinson's disease and essential tremor.

Twenty Parkinson's disease (PD) patients, 6 patients with essential tremor and 10 healthy controls were studied with the dopamine transporter ligand [(11)C]d-threo-methylphenidate ([(11)C]dMP) and positron emission tomography (PET) to assess dopamine terminal loss in relation to disease duration and motor disability. Dopamine transporter availability was expressed as [(11)C]dMP binding potential (BP(dMP)) in percentage of the mean of healthy controls. In PD patients (age at onset 57.7 +/- 8.9 yrs; disease duration 5.2 +/- 3.3 yrs; UPDRS motor score 24.2 +/- 9.8; Hoehn & Yahr 2.1 +/- 0.8; mean +/- SD) BP(dMP) was reduced to 30% (range: 11-55%) in the putamen and 52% (range: 14-96%) in the caudate nucleus. BP(dMP) in the putamen closely correlated with the UPDRS motor score (r = -0.79, p < 0.001), and disease duration (r = -0.76, p < 0.001) but not with age at onset. The correlation with the UPDRS score depended on akinesia and rigidity, while the tremor scores were related neither to putamen nor caudate BP(dMP). Interestingly, when plotted over disease duration, PD patients with severe asymmetry of symptoms showed significantly lower BP(dMP) in the contralateral putamen (exponential fit: 34% at onset) than the other PD patients (41% at onset), indicating a different symptomatic threshold of these subgroups and an even closer correlation with the hypothetical "true" disease duration. The exponential fit across all patients indicated a mean symptomatic threshold of 37% contra- and 62% ipsilateral, corresponding with an observed mean BP(dMP) of 51% (average contra- and ipsilateral) in those patients with disease duration less than one year. No differences in BP(dMP) were observed between patients with essential tremor and healthy controls. [(11)C]dMP appears to be a useful and sensitive marker of dopaminergic dysfunction in PD and can be used to assess and monitor disease severity.

A positron emission tomography (PET) study of cerebral dopamine D2 and serotonine 5-HT2A receptor occupancy in patients treated with cyamemazine (Tercian).

RATIONALE: Cyamemazine (Tercian) is an antipsychotic drug with anxiolytic properties. Recently, an in vitro study showed that cyamemazine possesses high affinity for serotonin 5-HT(2A) receptors, which was fourfold higher than its affinity for dopamine D(2) receptors (Hameg et al. 2003). OBJECTIVES: The aim of this study is to confirm these previous data in vivo in patients treated with clinically relevant doses of Tercian. METHODS: Eight patients received 37.5, 75, 150 or 300 mg/day of Tercian depending on their symptomatology. Dopamine D(2) and serotonin 5-HT(2A) receptor occupancies (RO) were assessed at steady-state plasma levels of cyamemazine with positron emission tomography (PET), using [(11)C]raclopride and [(11)C]N-methyl-spiperone, respectively. The effective plasma level of the drug leading to 50% of receptor occupancy was estimated by fitting RO with plasma levels of cyamemazine at the time of the PET scan. RESULTS: Cyamemazine induced near saturation of 5-HT(2A) receptors (RO=62.1-98.2%) in the frontal cortex even at low plasma levels of the drug. On the contrary, occupancy of striatal D(2) receptors increased with plasma levels, and no saturation was obtained even at high plasma levels (RO=25.2-74.9%). The effective plasma level of cyamemazine leading to 50% of D(2) receptor occupancy was fourfold higher than that for 5-HT(2A) receptors. Accordingly, individual 5-HT(2A)/D(2) RO ratios ranged from 1.26 to 2.68. No patients presented relevant increased prolactin levels, and only mild extrapyramidal side effects were noticed on Simpson and Angus Scale. CONCLUSION: This in vivo binding study conducted in patients confirms previous in vitro findings indicating that cyamemazine has a higher affinity for serotonin 5-HT(2A) receptors compared to dopamine D(2) receptors. In the dose range 37.5-300 mg, levels of dopamine D(2) occupancy remained below the level for motor side effects observed with typical antipsychotics and is likely to explain the low propensity of the drug to induce extrapyramidal side effects.

Preparation of the hypoxia imaging PET tracer [18F]FAZA: reaction parameters and automation.

18F-labeling of the nitroimidazole nucleoside analogue 1-(5-fluoro-5-deoxy-alpha-D-arabinofuranosyl)-2-nitroimidazole (FAZA) was developed to use this tracer in PET for detection of hypoxia. Parameters for labeling and hydrolysis were optimized with regard to amount of precursor, temperature and time. Labeling yields reached a maximum of 62+/-4% at 100 degrees C within 5 min using 5 mg of precursor. Hydrolysis was best performed with 1 mL of 0.1 N NaOH at 20 degrees C for 2 min. Transfer of these conditions to an automated synthesizer resulted in an overall radiochemical yield of 20.7+/-3.5%. Absolute yields at EOS were 9.8+/-2.3 GBq of [18F]FAZA ready for injection (n=21; 50 min after EOB; irradiation parameters: 35 microA, 60 min). Thus, a convenient approach suitable for large-scale production of [18F]FAZA was developed by an automated process.

Efficient radiosynthesis of carbon-11 labelled uncharged Thioflavin T derivatives using [11C]methyl triflate for beta-amyloid imaging in Alzheimer's Disease with PET.

The synthesis of carbon-11 amino function labelled uncharged Thioflavin T derivatives is known to be performed by reaction of the demethyl-precursors with [11C]methyl iodide but the labelling yields are only mediocre. The use of [11C]methyl triflate improved the radiochemical yield of three potential beta-amyloid imaging PET-radiotracers significantly. Performance of the labelling reaction by reacting the corresponding precursor molecules with [11C]methyl triflate for 1 min at 80 degrees C led to radiochemical yields of 44+/-10% (n=5) for [11C]6-Me-BTA-1, 68+/-4% (n=10) for [11C]BTA-1 and 58+/-2% (n=5) for [11C]6-OH-BTA-1 with respect to [11C]methyl triflate. In production runs (60 min, 50 microA) up to 6500 MBq (mean: 4000+/-1900 MBq) of [11C]6-Me-BTA-1, 7900 MBq (mean: 6000+/-1000 MBq) of [11C]BTA-1 and 7100 MBq (mean: 6300+/-600 MBq) of [11C]6-OH-BTA-1 could be obtained ready for intravenous injection. The radiochemical purity was >95% with specific activities in the range of 80-120 GBq/micromol (EOS) within a total synthesis time of less than 40 min after EOB.

Highly efficient automated synthesis of [(11)C]choline for multi dose utilization.

[(11)C]Choline has been under investigation as a PET ligand for imaging tumor tissue, especially prostate cancer. An improved, automated synthesis of the tracer now was established. [(11)C] Choline was produced by labeling 2-(dimethylamino)-ethanol (DMAE) with [(11)C]CH(3)I in a Tefzel tube at room temperature without solvent. The product was purified using a cation exchange cartridge. Reaction conditions were optimized with respect to synthesis time and amount of DMAE, resulting in radiochemical yields higher than 80% using 60 microl of DMAE in 20 min, radiochemical purity was >99% and residual DMAE was below 10 ppm. After (11)C-production of 1h at 50 microA [(11)C]choline activities of 30.0+/-5.6 GBq (n = 29) were obtained in sterile solution ready for intravenous administration.

Non-invasive assessment of distribution volume ratios and binding potential: tissue heterogeneity and interindividually averaged time-activity curves.

Due to the stochastic nature of radioactive decay, any measurement of radioactivity concentration requires spatial averaging. In pharmacokinetic analysis of time-activity curves (TAC), such averaging over heterogeneous tissues may introduce a systematic error (heterogeneity error) but may also improve the accuracy and precision of parameter estimation. In addition to spatial averaging (inevitable due to limited scanner resolution and intended in ROI analysis), interindividual averaging may theoretically be beneficial, too. The aim of this study was to investigate the effect of such averaging on the binding potential ( BP) calculated with Logan's non-invasive graphical analysis and the "simplified reference tissue method" (SRTM) proposed by Lammertsma and Hume, on the basis of simulated and measured positron emission tomography data [[(11)C] d- threo-methylphenidate (dMP) and [(11)C]raclopride (RAC) PET]. dMP was not quantified with SRTM since the low k(2) (washout rate constant from the first tissue compartment) introduced a high noise sensitivity. Even for considerably different shapes of TAC (dMP PET in parkinsonian patients and healthy controls, [(11)C]raclopride in patients with and without haloperidol medication) and a high variance in the rate constants (e.g. simulated standard deviation of K(1)=25%), the BP obtained from average TAC was close to the mean BP (error <5%). However, unfavourably distributed parameters, especially a correlated large variance in two or more parameters, may lead to larger errors. In Monte Carlo simulations, interindividual averaging before quantification reduced the variance from the SRTM (beyond a critical signal to noise ratio) and the bias in Logan's method. Interindividual averaging may further increase accuracy when there is an error term in the reference tissue assumption E= DV(2)- DV' ( DV(2) = distribution volume of the first tissue compartment, DV' = distribution volume of the reference tissue). This can be explained by the fact that the distribution volume ratio ( DVR= DV/DV') obtained from averaged TAC is an approximation for Sigma DV/Sigma DV' rather than for Sigma DVR/ n. We conclude that Logan's non-invasive method and SRTM are suitable for heterogeneous tissues and that discussion of group differences in PET studies generally should include qualitative and quantitative assessment of interindividually averaged TAC.

Electrochemical radiofluorination. Part 2. Anodic monofluorination of substituted benzenes using [18F]fluoride.

Electrochemical fluorination of various monosubstituted aromatic compounds was performed with [18F]fluoride using potentiostatic anodic oxidation on platinum electrodes in an undivided cell in acetonitrile with a mixture of Et(3)N.3HF/Et(3)N.HCl as electrolyte. Maximum radiochemical yields were obtained after a charge of 50C passed the solution. The results showed a clear dependence of the radiochemical yields on the oxidation potentials E(1/2) of the substrates as a consequence of different substituents namely CH(3)CO-, F-, Cl-, Br- and tert.-Butyl. With increasing E(1/2), the fluorination yields decreased from 7.9% (tert.-butylbenzene) to 1.5% (acetophenone). The ratio between F-for-X substitution and F-for-H substitution correlated with the bond energies of the C-X bond. With higher bond energies, less X-substitution was observed.