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BACKGROUND: Clinical positron emission tomography (PET) requires safe and effective PET radiopharmaceuticals. Tracers used for measuring oxygen consumption and blood volume are [(15)O]O(2) and [(15)O]CO, respectively. In general, these oxygen-15 labelled tracers are produced using a cyclotron that accelerates deuterons onto a target filled with (14)N(2) containing a trace of oxygen. In recent years, cyclotrons have been developed that only are capable of accelerating protons. The purpose of this study was to validate and assess such a cyclotron for production and administration of oxygen-15 labelled gasses in an hospital setting.METHODS: An RDS111 cyclotron (Siemens-CTI, Knoxville, USA) was validated for bolus production of [(15)O]O(2) and [(15)O]CO gasses. In addition, equipment was developed to administer these tracers to patients.RESULTS: Both [(15)O]O(2) and [(15)O]CO gasses could be produced in sufficient amounts, whilst meeting European Pharmacopeia requirements. Although produced oxygen-15 gasses contained a minor level of (11)C contamination, in clinical studies it was possible to correct for this contamination by delayed blood counting.CONCLUSION: An 11 MeV proton cyclotron combined with an in-house developed gas delivery system allows for the production and administration of sufficient amounts of [(15)O]-gasses for routine clinical PET studies in an hospital setting.

Objective The objectives of the study were to develop a population pharmacokinetic model for 11C-flumazenil at tracer concentrations, to assess the effects of patient-related covariates and to derive an optimal sampling protocol for clinical use. Methods A population pharmacokinetic model was developed using nonlinear mixed effects modelling (NONMEM) with data obtained from 51 patients with either depression or epilepsy. Each patient received ∼370 MBq (1–4 µg) of 11C-flumazenil. The effects of selected covariates (gender, weight, type of disease and age) were investigated. The model was validated using a bootstrap method. Finally, an optimal sampling design was established. Results The population pharmacokinetics of tracer quantities of 11C-flumazenil were best described by a two compartment model. Type of disease and weight were identified as significant covariates (P

[11C]-Flumazenil is a radiopharmaceutical that can be used to quantify benzodiazepine receptor concentrations and drug binding in the human brain using positron emission tomography (PET). In PET studies, arterial blood sampling is required to correct for labelled metabolites in plasma. The metabolite corrected arterial plasma curve of [11C]-flumazenil is used as the input function for the receptor pharmacokinetic model in clinical PET studies. The main metabolic pathway for flumazenil is conversion to flumazenil ‘acid’ by hepatic carboxylesterases. Interestingly, carboxylesterases are also involved in the bioconversion of other ester-type drugs such as cocaine, acetylsalicylic acid and many cholesterol synthesis inhibitors. Thus far, little is known about (genetic) differences in carboxylesterase activities. In principle, flumazenil may serve as a marker substrate for carboxylesterase phenotyping and predict metabolism for these kinds of drugs. The aim was to study interindividual differences in flumazenil clearance and flumazenil ‘acid’ formation in healthy volunteers and CNS patients. Healthy volunteers and CNS patients (n=25) participating in different PET protocols were included. During PET scanning, arterial blood samples were collected for ex vivo counting and metabolite analysis at 7 time-points. The plasma samples were analysed by reversed phase h.p.l.c. with radioactivity detection, as previously described [1]. The data were fitted by a commercially available and previously validated pharmacokinetic computer program (MW\Pharm, MediWare BV, Groningen, The Netherlands). The total body clearance (CL), volume of distribution (Vd) and the elimination rate constant (k10) were calculated for flumazenil pharmacokinetics. Parent flumazenil clearance from the plasma compartment was best fitted with a 2-compartment model (r2>0.98). The plasma clearance ranged from 48–139 l h−1. The flumazenil ‘acid' curve was fitted by an extravascular, 1-compartment model (r2>0.98). The rate constant of metabolite formation (km) ranged from 2.4–24 h−1, indicating pronounced interindividual differences in flumazenil ‘acid' formation. The total body clearance of this tracer dose of flumazenil is in the range of earlier reported pharmacological doses ([2]; Table 1). The estimated hepatic extraction ratio (EH) was 0.6–0.8 (assuming a hepatic blood flow of 60–90 l h−1). The rate of flumazenil ‘acid' formation correlated with the clearance of flumazenil, suggesting a major role of hepatic carboxylesterases in flumazenil clearance. Table 1. Pharmacokinetics of parent [11C]-flumazenil. Tracer dose Pharmacological dose Range Mean Clearance (l h−1) 48–139 76 ± 23 30–78 Vd (l kg−1) n.d. 0.78 (n.d.) 0.6–1.1 k10 (h−1) 1.7–25 4.6 ± 4.6 n.d. EH 0.6–0.8 n.d. 0.6 The plasma pharmacokinetics of [11C]-flumazenil show pronounced interindividual variation. The relative high hepatic extraction ratio implicates that the formation of flumazenil ‘acid' depends on the functional status of liver cells (carboxylesterase activity) and also on hepatic blood flow. Input curves of [11C]-flumazenil should be corrected for labelled metabolites on an individual basis. Interindividual differences in flumazenil handling may reflect the variation in drug metabolism of ester-type drugs.

3059 Background: Current strategies combining anti-angiogenic drugs with chemotherapy provide clinical benefit in patients with advanced-stage NSCLC cancer. It has been hypothesized that pre-treatment with anti-angiogenic drugs may transiently normalize abnormal tumor vasculature and contribute to improved delivery of subsequent chemotherapy (Nat Med 2001;7:987-9). The purpose of the present study was to investigate this concept in NSCLC patients using a perfusion tracer ([15O]H2O), radiolabeled chemotherapy ([11C]docetaxel) and positron emission tomography (PET) before and after a single infusion of bevacizumab. Methods: A total of 70 PET scans were scheduled in 10 NSCLC patients. Patients underwent dynamic PET scans with [15O]H2O and [11C]docetaxel before, and at 5 hours and 4 days after IV administration of bevacizumab (15 mg·kg-1). An additional [15O]H2O scan was performed at 2 hours. Systemic effects of bevacizumab were investigated by assessing: (1) plasma levels of vascular endothelial growth facto...

2543 Background: Although docetaxel is an effective treatment of lung cancer, a number of patients do not benefit from this therapy due to tumor resistance. Positron emission tomography (PET) is a ...