Radiosynthesis of carbon-11 labeled 6-methyldopamine ([¹¹C]MeDA).

A rapid and efficient n.c.a. radiosynthesis of 6-[(11)C]methyldopamine ([(11)C]MeDA) using the Stille cross-coupling reaction as a key step was developed. The labeling conditions for the formation of the intermediate compound (protected [(11)C]MeDA, [(11)C]7) were determined with respect to reaction temperature and time. The radiochemical yield 89 ± 1.4% (decay-corrected) of the protected intermediate [(11)C]7 was obtained at a reaction temperature of 60°C and a reaction time of 5 min using Pd(2)(dba)(3)/P(o-tolyl)(3) and CsF/CuBr as a co-catalyst system. The overall yield after deprotection with 45% HBr at 140°C for 10 min was 64 ± 3.9% (decay-corrected) within a total preparation time of 40 min, including hydrolysis, HPLC purification and formulation.

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.

Production of [11C]chloroform by direct chlorination of [11C]methane without catalyst support for the synthesis of [11C]diazomethane.

The preparation of [11C]chloroform by direct chlorination of [11C]methane using gaseous chlorine by variation of temperature and reaction time (inert gas flow) without catalyst support for the online production of [11C]diazomethane in a flow-through synthesis apparatus is described in this work. At an oven temperature of 400 degrees C and a He flow of 50 mL/min, [11C]chloroform was synthesized inside a quartz glass column in a radiochemical yield of 31+/-2% with respect to [11C]methane. The online preparation of [11C]diazomethane by reaction of [11C]chloroform with hydrazine in an ethanolic KOH solution with small amounts of 18-crown-6-crownether succeeded with a radiochemical yield of 20+/-3% with respect to [11C]methane. The product [11C]diazomethane was measured indirectly in the form of 4-nitrobenzoic acid[11C]methylester using the esterification of 4-nitrobenzoic acid as a monitor reaction.

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.

Occupancy of dopamine D(1), D (2) and serotonin (2A) receptors in schizophrenic patients treated with flupentixol in comparison with risperidone and haloperidol.

RATIONALE: Flupentixol (FLX) has been used as a neuroleptic for nearly 4 decades. In vitro data show comparable affinity to dopamine D(2), D(1) and 5-HT(2A) receptors and recently, FLX showed to be not inferior to risperidone in schizophrenic patients with predominant negative symptomatology, which was implicated with flupentixol's interaction with 5-HT(2A) and/or D(1) receptors. OBJECTIVES: To assess in vivo receptor occupancy (RO) in patients clinically treated with FLX (n = 13, 5.7 +/- 1.4 mg/day) in comparison with risperidone (RIS, n = 11, 3.6 +/- 1.3 mg/day) and haloperidol (HAL, n = 11, 8.5 +/- 5.5 mg/day). MATERIALS AND METHODS: Each patient underwent two PET scans with 3-N-[(11)C]methylspiperone (target: frontal 5-HT(2A)), [(11)C]SCH23390 (striatal D(1)) or [(11)C]raclopride (striatal D(2)). RO was calculated as the percentage reduction of specific binding in comparison with healthy controls. RESULTS: D(2)-RO under FLX was between 50% and 70%, indicating an ED(50) of about 0.7 ng/ml serum. 5-HT(2A) and D(1)-RO was 20 +/- 10% and 20 +/- 5% (mean, SEM). Under HAL, D(1)-RO was 14 +/- 6% and under RIS not significantly different from zero. CONCLUSIONS: We were able to demonstrate a moderate 5-HT(2A) and D(1) occupancy under clinically relevant doses of flupentixol, albeit lower than expected from in vitro data and clearly below saturation. Therefore, if flupentixol's efficacy on negative symptoms is based on its interaction with 5-HT(2A) and/or D(1) receptors, it should be highly dependent on serum concentration and thus on dosage and metabolism. However, these data suggest that mechanisms other than D(1) or 5-HT(2A) antagonism may contribute to flupentixol's efficacy on negative symptoms.

Spinocerebellar ataxia type 1, 2, and 3 and restless legs syndrome: striatal dopamine D2 receptor status investigated by [11C]raclopride positron emission tomography.

In spinocerebellar ataxias (SCAs), up to 30% of patients complain of restless legs syndrome (RLS). In primary RLS, a putative role of the dopaminergic system has been postulated. To assess dopaminergic function in SCA1, 2, and 3, dopamine D(2) receptor binding potential (BP) was assessed by [(11)C]raclopride positron emission tomography in 10 SCA patients, 4 of whom suffered from RLS as demonstrated by polysomnography. BP was compared to 9 age-matched control subjects. In 2 SCA patients, striatal BP was clearly reduced (<2 SD below the mean of controls). However, there were no significant group differences between SCA and controls, largely owing to a significantly higher variance of striatal BP in SCA. BP was negatively correlated with disease duration. The fit suggests an increased BP in early stages, followed by a moderate decline in all quantified regions (caudate, dorsal putamen, ventral striatum) presumably reflecting a progressive loss of D(2) receptors. RLS in SCA was not accompanied by a significant reduction of D(2) receptor availability in the striatum. This missing correlation may point to an extrastriatal origin of RLS.

Synthesis, physicochemical characterization and preliminary pharmacological in vitro evaluation of two novel cytotoxic benzophenone-linked 3,3-dimethyltriazenes.

The synthesis, physicochemical characterization and preliminary pharmacological evaluation of the cytotoxic effects of two novel substances, 1-(4-benzoylphenyl)-3,3-dimethyltriazene and 1-(2-benzoylphenyl)-3,3-dimethyltriazene is presented. The cytotoxicity of the novel benzophenone-linked triazenes and of ten other 1-phenyl-3,3-dimethyl triazene derivatives as well as of the referent alkylating drug melphalan was assessed using the MTT-dye reduction assay. A panel of human tumor cell lines was used: the chronic lymphoid leukemia SKW-3, the acute promyelocyte leukemia HL-60 and its multi-drug-resistant subline HL-60/Dox. Both novel compounds showed strong cytotoxic activity, comparable to that of the referent alkylating agent melphalan, whereas the ten ring-substituted 1-phenyl-3,3-dimethyl triazenes proved to be far less active in vitro. DNA-fragmentation analysis indicated that after 24 h treatment the novel benzophenone-linked triazenes induced programmed cell death in HL-60 cells.

Is standardised (18)F-FDG uptake value an outcome predictor in patients with stage III non-small cell lung cancer?

PURPOSE: Recent studies have demonstrated the relevance of (18)F-FDG uptake as an independent prognostic factor for recurrence of operable non-small cell lung cancer (NSCLC). This corresponds with the experimental finding that FDG uptake correlates with the proliferative activity of tumour cells (Higashi et al., J Nucl Med 2000;41:85-92). On the basis of these observations, we studied the influence of FDG uptake on prognosis and occurrence of distant metastases in patients with advanced NSCLC. METHODS: One hundred and fifty-nine patients with NSCLC of UICC stage IIIA or IIIB were included in the study. In all patients, neoadjuvant treatment was planned to achieve operability. FDG PET was performed as an additional staging procedure prior to the initiation of therapy. Clinical outcome data in terms of overall survival, disease-free survival and incidence of distant metastases could be obtained for 137 patients and were correlated with the average standardised uptake value of the tumour (SUV(avg)). Furthermore, other factors influencing SUV(avg) and patient outcome (histological tumour type, grading, UICC stage, tumour size) were analysed. RESULTS: SUV(avg) was significantly influenced by tumour histology, UICC stage and tumour size. No significant difference could be shown for grading. In 38 out of the 159 patients (24%), FDG PET revealed previously unsuspected distant metastases. The incidence of distant metastases significantly correlated with SUV(avg). Overall survival tended to decrease with increasing SUV(avg); however, significance was only reached when a cut-off of 12.0 was applied (p=0.05). CONCLUSION: FDG uptake is an independent prognostic factor in patients with UICC stage III NSCLC, although less distinctively so than has been reported for stage I/II tumours.

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.

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.

On biologically conformal boost dose optimization.

A method is described that allows the inclusion of biological imaging data in the optimization of intensity-modulated radiotherapy to produce dose boosts that conform with target subvolumes of potentially reduced radiosensitivity. The biological image (e.g. PET, fMRI, etc) is transformed into a dose efficiency distribution using a piecewise linear calibration function with a prescribed maximum boost factor. Instead of dose alone, the cost function of the optimization algorithm depends on the product of the physical dose times dose efficiency. An example case of a base-of-tongue tumour which was imaged with the hypoxia tracer fluoro-misonidazole is presented, showing the excellent capability of IMRT to produce dose distributions that conform to spatially variable dose prescriptions.

Assessment of porcine bone metabolism by dynamic.

UNLABELLED: The aim of this study was to quantify regional bone blood flow and [(18)F]fluoride ion influx with [(18)F]fluoride ion PET and correlate the results with specific static and dynamic indices of bone metabolism in healthy pigs. METHODS: During continuous ventilation (fractional concentration of oxygen in inspired gas = 0.3), dynamic PET scans 120 min in duration were obtained for 9 mini pigs after intravenous injection of 10.0 +/- 1.2 MBq (mean +/- SD) of [(18)F]fluoride ion per kilogram of body weight. Iliac crest bone biopsies were performed immediately before the PET scan to determine static and dynamic indices of bone metabolism (i.e., the mineral apposition rate) by bone histomorphometry. Kinetic rate constants describing influx (K(1)) and efflux (k(2)) of [(18)F]fluoride as well as chemisorption and incorporation of [(18)F]fluoride (k(3)) and reverse transport (k(4)) were determined for 6 vertebral bodies in each animal. Blood flow estimates (f) were derived from K(1) values corrected for the permeability-surface area product using a previously derived correction algorithm. A rate constant describing the net forward transport rate of fluoride (K(i)) and the fluoride volume flux (K(flux)) derived from a 2-tissue-compartment model was calculated and compared with the results of Patlak graphic analysis (K(pat)). RESULTS: A significant correlation was found between mineral apposition rate and K(i) (P < 0.005), K(flux) (P < 0.01), K(pat), K(1), and f (P < 0.05). The values of f, K(i), K(flux), and K(pat) did not correlate significantly with other static or dynamic histomorphometric indices or with age, serum alkaline phosphatase, or parathyroid hormone levels. The values of f and K(i) correlated linearly (y = 0.023 + 0.32x; r(2) = 0.74; P < 0.001). CONCLUSION: PET bone studies using [(18)F]fluoride ion provide quantitative estimates of bone blood flow and metabolic activity that correlate with histomorphometric indices of bone formation in the normal bone tissue of the mini pig. Therefore, it seem reasonable to assume that [(18)F]fluoride ion PET can reduce the number of invasive bone biopsies, thus facilitating follow-up of patients with metabolic bone diseases.

Neuroimaging in alcoholism: ethanol and brain damage.

This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The co-chairs were Karl Mann and Ingrid Agartz. The presentations were (1) Neuropathological changes in alcohol-related brain damage, by Clive Harper; (2) Regional brain volumes including the hippocampus and monoamine metabolites in alcohol dependence, by Ingrid Agartz, Susan Shoaf, Robert R, Rawlings, Reza Momenan, and Daniel W Hommer; (3) Diffusion tensor abnormalities in imaging of white matter alcoholism, by Adolf Pfefferbaum and Edith V. Sullivan; (4) Use of functional MRI to evaluate brain activity during alcohol cue exposure in alcoholics: Relationship to craving, by Raymond F. Anton, David J. Drobes, and Mark S. George; and (5) mu-Opiate receptor availability in alcoholism: First results from a positron emission tomography study, by Karl Mann, Roland Bares, Hans-Juergen Machulla, Goetz Mundle, Matthias Reimold, and Andreas Heinz.

Dependency of the [18F]fluoromisonidazole uptake on oxygen delivery and tissue oxygenation in the porcine liver.

We have previously shown that the accumulation of fluorine-18-labeled fluoromisonidazole ([(18)F]FMISO) is inversely correlated to tissue oxygenation, allowing the quantification of porcine liver tissue hypoxia in vivo. We determined the activity from administered [(18)F]FMISO in relation to the hepatic oxygen availability and the partial pressure of oxygen in tissue (tPO(2)) to define a critical oxygen delivery on a regional basis. [(18)F]FMISO was injected 2 h after onset of regional liver hypoxia due to arterial occlusion of branches of the hepatic artery in 10 domestic pigs. During the experimental procedure the fractional concentration of inspired oxygen (FiO(2)) was set to 0.67 in group A ( N=5) and to 0.21 in group B ( N=5) animals. Immediately before sacrifice, the tPO(2) was determined in normal flow and flow-impaired liver segments. The standardized uptake values (SUV) for [(18)F]FMISO was calculated from 659 single tissue samples obtained 3 h after injection of approximately 10 MBq/kg body weight [(18)F]FMISO and was compared with the regional total hepatic oxygen delivery (DO(2)) calculated from the regional arterial and portal venous flow (based on (141)Ce- and (99m)Tc-microspheres measurements) and the oxygen content of the arterial and portal venous blood. In 121 tPO(2)-measured liver tissue samples, the mean DO(2) was significantly decreased in occluded liver tissue samples [group A: 0.063 (0.044-0.089); group B: 0.046 (0.032-0.066)] compared to normal flow segments [group A: 0.177 (0.124-0.252); group B: 0.179 (0.128-0.25) mL x min(-1) x g(-1); geometric mean (95% confidence limits); p < 0.01 in group A and p < 0.001 in group B]. The tPO(2) of occluded segments [group A: 5.1 (3.2-8.1); group B: 3.9 (2.4-6.2) mm Hg] was significantly decreased compared to normal flow segments [group A: 20.2 (12.6-32.5); group B: 22.4 (14.3-35.2) mm Hg; p < 0.01 in group A and p < 0.001 in group B]. Three hours after [(18)F]FMISO administration, the mean [(18)F]FMISO SUV determined in tPO(2)-measured occluded segments was significantly higher [group A: 4.08 (3.12-5.34), group B: 5.43 (4.14-7.13)] compared to normal liver tissue [group A: 1.57 (1.2-2.06), group B: 1.5 (1.16-1.93); p < 0.001 for both groups]. The [(18)F]FMISO SUV allowed prediction of the tPO(2) with satisfying accuracy in hypoxic regions using the exponential regression curve [[(18)F]FMISO=1.05+6.7((-0.117 tPO(2))); r(2)=0.75; p < 0.001]. In addition, regardless of ventilation conditions, a significant exponential relationship between the DO(2) and the [(18)F]FMISO SUV was found ( r(2)=0.39, p < 0.001). Our results suggest that the reduction of the oxygen delivery below the critical range of 0.1-0.11 mL x min(-1) x g(-1) regularly causes liver tissue hypoxia. The severity of hypoxia is reflected by the [(18)F]FMISO accumulation and allows the in vivo estimation of the tPO(2) in hypoxic regions.