Uptake of inflammatory cell marker [<Superscript>11</Superscript>C]PK11195 into mouse atherosclerotic plaques

Purpose  The ligand [¹¹C]PK11195 binds with high affinity and selectivity to peripheral benzodiazepine receptor, expressed in high amounts in macrophages. In humans, [¹¹C]PK11195 has been used successfully for the in vivo imaging of inflammatory processes of brain tissue. The purpose of this study was to explore the feasibility of [¹¹C]PK11195 in imaging inflammation in the atherosclerotic plaques. Methods  The presence of PK11195 binding sites in the atherosclerotic plaques was verified by examining the in vitro binding of [³H]PK11195 onto mouse aortic sections. Uptake of intravenously administered [¹¹C]PK11195 was studied ex vivo in excised tissue samples and aortic sections of a LDLR/ApoB48 atherosclerotic mice. Accumulation of the tracer was compared between the atherosclerotic plaques and non-atherosclerotic arterial sites by autoradiography and histological analyses. Results  The [³H]PK11195 was found to bind to both the atherosclerotic plaques and the healthy wall. The autoradiography analysis revealed that the uptake of [¹¹C]PK11195 to inflamed regions in plaques was more prominent (p = 0.011) than to non-inflamed plaque regions, but overall it was not higher than the uptake to the healthy vessel wall. Also, the accumulation of ¹¹C radioactivity into the aorta of the atherosclerotic mice was not increased compared to the healthy control mice. Conclusions  Our results indicate that the uptake of [¹¹C]PK11195 is higher in inflamed atherosclerotic plaques containing a large number of inflammatory cells than in the non-inflamed plaques. However, the tracer uptake to other structures of the artery wall was also prominent and may limit the use of [¹¹C]PK11195 in clinical imaging of atherosclerotic plaques.     

Kinetic analysis of the translocator protein positron emission tomography ligand [<Superscript>18</Superscript>F]GE-180 in the human brain

Purpose

PET can image neuroinflammation by targeting the translocator protein (TSPO), which is upregulated in activated microglia. The high nonspecific binding of the first-generation TSPO radioligand [¹¹C]PK-11195 limits accurate quantification. [¹⁸F]GE-180, a novel TSPO ligand, displays superior binding to [¹¹C]PK-11195 in vitro. Our objectives were to: (1) evaluate tracer characteristics of [¹⁸F]GE-180 in the brains of healthy human subjects; and (2) investigate whether the TSPO Ala147Thr polymorphism influences outcome measures.

Methods

Ten volunteers (five high-affinity binders, HABs, and five mixed-affinity binders, MABs) underwent a dynamic PET scan with arterial sampling after injection of [¹⁸F]GE-180. Kinetic modelling of time–activity curves with one-tissue and two-tissue compartment models and Logan graphical analysis was applied to the data. The primary outcome measure was the total volume of distribution (V _T) across various regions of interest (ROIs). Secondary outcome measures were the standardized uptake values (SUV), the distribution volume and SUV ratios estimated using a pseudoreference region.

Results

The two-tissue compartment model was the best model. The average regional delivery rate constant (K ₁) was 0.01 mL cm^?3 min^?1 indicating low extraction across the blood–brain barrier (1 %). The estimated median V _T across all ROIs was also low, ranging from 0.16 mL cm^?3 in the striatum to 0.38 mL cm^?3 in the thalamus. There were no significant differences in V _T between HABs and MABs across all ROIs.

Conclusion

A reversible two-tissue compartment model fitted the data well and determined that the tracer has a low first-pass extraction (approximately 1 %) and low V _T estimates in healthy individuals. There was no observable dependency on the rs6971 polymorphism as compared to other second-generation TSPO PET tracers. Investigation of [¹⁸F]GE-180 in populations with neuroinflammatory disease is needed to determine its suitability for quantitative assessment of TSPO expression.

     

The effects of <Emphasis Type="Italic">d</Emphasis>-amphetamine on extrastriatal dopamine D<Subscript>2</Subscript>/D<Subscript>3</Subscript> receptors: a randomized,double-blind,placebo-controlled PET study with [<Superscript>11</Superscript>C]FLB 457 in healthy subjects

Purpose  The dopamine D₂/D₃ receptor ligand [¹¹C]FLB 457 and PET enable quantification of low-density extrastriatal D₂/D₃ receptors, but it is uncertain whether [¹¹C]FLB 457 can be used for measuring extrastriatal dopamine release. Methods  We studied the effects of d-amphetamine (0.3 mg/kg i.v.) on extrastriatal [¹¹C]FLB 457 binding potential (BP_ND) in a randomized, double-blind, placebo-controlled study including 24 healthy volunteers. Results  The effects of d-amphetamine on [¹¹C]FLB 457 BP_ND and distribution volume (V_T) in the frontal cortex were not different from those of placebo. Small decreases in [¹¹C]FLB 457 BP_ND were observed only in the posterior cingulate and hippocampus. The regional changes in [¹¹C]FLB 457 BP_ND did not correlate with d-amphetamine-induced changes in subjective ratings of euphoria. Conclusion  This placebo-controlled study showed that d-amphetamine does not induce marked changes in measures of extrastriatal dopamine D₂/D₃ receptor binding. Our results indicate that [¹¹C]FLB 457 PET is not a useful method for measuring extrastriatal dopamine release in humans.     

Image-derived input functions for PET brain studies

Purpose  To assess the robustness of a previously introduced method to obtain accurate image-derived input functions (IDIF) for three other tracers. Methods  Dynamic PET and online blood data of five repeat [¹¹C]PIB (Pittsburgh Compound-B) ([¹¹C]PIB), six repeat (R)-[¹¹C]verapamil, and ten single (R)-[¹¹C]PK11195 studies were used. IDIFs were extracted from partial volume corrected scans using the four hottest pixels per plane method. Results obtained with IDIFs were compared with those using standard online measured arterial input functions (BSIF). IDIFs were used both with and without calibration based on manual blood samples. Results  For (R)-[¹¹C]verapamil, accurate IDIFs were obtained using noncalibrated IDIFs (slope 0.96±0.17; R ² 0.92±0.07). However, calibration was necessary to obtain IDIFs comparable to the BSIF for both [¹¹C]PIB (slope 1.04±0.05; R ² 1.00±0.01) and (R)-[¹¹C]PK11195 (slope 0.96±0.05; R ² 0.99±0.01). The need for calibration may be explained by the sticking property of both tracers, indicating that BSIF may be affected by sticking and therefore may be unreliable. Conclusion  The present study shows that a previously proposed method to extract IDIFs is suitable for analysing [¹¹C]PIB, (R)-[¹¹C]verapamil and (R)-[¹¹C]PK11195 studies, thereby obviating the need for online arterial sampling.     

Detection of gastric cancer using <Superscript>18</Superscript>F-FLT PET: comparison with <Superscript>18</Superscript>F-FDG PET

Purpose  We prospectively investigated the feasibility of 3′-deoxy-3′-¹⁸F-fluorothymidine (FLT) positron emission tomography (PET) for the detection of gastric cancer, in comparison with 2-deoxy-2-¹⁸F-fluoro-d-glucose (FDG) PET, and determined the degree of correlation between the two radiotracers and proliferative activity as indicated by Ki-67 index. Methods  A total of 21 patients with newly diagnosed advanced gastric cancer were examined with FLT PET and FDG PET. Tumour lesions were identified as areas of focally increased uptake, exceeding that of surrounding normal tissue. For semiquantitative analysis, the maximal standardized uptake value (SUV) was calculated. Results  For detection of advanced gastric cancer, the sensitivities of FLT PET and FDG PET were 95.2% and 95.0%, respectively. The mean (±SD) SUV for FLT (7.0 ± 3.3) was significantly lower than that for FDG (9.4 ± 6.3 p < 0.05). The mean FLT SUV and FDG SUV in nonintestinal tumours were higher than in intestinal tumours, although the difference was not statistically significant. The mean (±SD) FLT SUV in poorly differentiated tumours (8.5 ± 3.5) was significantly higher than that in well and moderately differentiated tumours (5.3 ± 2.1; p < 0.04). The mean FDG SUV in poorly differentiated tumours was higher than in well and moderately differentiated tumours, although the difference was not statistically significant. There was no significant correlation between Ki-67 index and either FLT SUV or FDG SUV. Conclusion  FLT PET showed as high a sensitivity as FDG PET for the detection of gastric cancer, although uptake of FLT in gastric cancer was significantly lower than that of FDG.     

Kinetic modelling of [<Superscript>11</Superscript>C]flumazenil using data-driven methods

Purpose  [¹¹C]Flumazenil (FMZ) is a benzodiazepine receptor antagonist that binds reversibly to central-type gamma-aminobutyric acid (GABA-A) sites. A validated approach for analysis of [¹¹C]FMZ is the invasive one-tissue (1T) compartmental model. However, it would be advantageous to analyse FMZ binding with whole-brain pixel-based methods that do not require a-priori hypotheses regarding preselected regions. Therefore, in this study we compared invasive and noninvasive data-driven methods (Logan graphical analysis, LGA; multilinear reference tissue model, MRTM2; spectral analysis, SA; basis pursuit denoising, BPD) with the 1T model. Methods  We focused on two aspects: (1) replacing the arterial input function analyses with a reference tissue method using the pons as the reference tissue, and (2) shortening the scan protocol from 90 min to 60 min. Dynamic PET scans were conducted in seven healthy volunteers with arterial blood sampling. Distribution volume ratios (DVRs) were selected as the common outcome measure. Results  The SA, LGA with and without arterial input, and MRTM2 agreed best with the 1T model DVR values. The invasive and noninvasive BPD were slightly less well correlated. The full protocol of a 90-min emission data performed better than the 60-min protocol, but the 60-min protocol still delivered useful data, as assessed by the coefficient of variation, and the correlation and bias analyses. Conclusion  This study showed that the SA, LGA and MRTM2 are valid methods for the quantification of benzodiazepine receptor binding with [¹¹C]FMZ using an invasive or noninvasive protocol, and therefore have the potential to reduce the invasiveness of the procedure.     

A Single Intraperitoneal Injection of Endotoxin Changes Glial Cells in Rats as Revealed by Positron Emission Tomography Using [<Superscript>11</Superscript>C]PK11195

Purpose

Intracranial administration of lipopolysaccharide (LPS) is known to elicit a rapid innate immune response, activate glial cells in the brain, and induce depression-like behavior. However, no study has focused on the changes in glial cells induced by intraperitoneal injection of LPS in vivo.

Methods

Ten adult male Fischer F344 rats underwent [¹¹C]PK11195 PET before and 2 days after intraperitoneal injection of LPS to evaluate the changes in glial cells. The difference in standardized uptake values (SUV) of [¹¹C]PK11195 between before and after injection was determined.

Results

There was a cluster of brain regions that showed significant reductions in SUV. This cluster included the bilateral striata and bilateral frontal regions, especially the somatosensory areas.

Conclusions

Changes in activity of glial cells induced by the intraperitoneal injection of LPS were detected in vivo by [¹¹C]PK11195 PET. Intraperitoneal injection of LPS is known to induce depression, and further studies with [¹¹C]PK11195 PET would clarify the relationships between neuroinflammation and depression.

     

Kinetics of [<Superscript>11</Superscript>C]choline uptake in prostate cancer: a PET stydy

Carbon-11 choline has recently been introduced as a potential tracer for tumour imaging with positron emission tomography (PET). We evaluated the kinetics of the uptake of [¹¹C]choline in prostate cancer and benign prostatic hyperplasia. We also evaluated the association between the uptake of [¹¹C]choline and the histological grade of malignancy, Gleason score, volume of the prostate and prostate-specific antigen (PSA). Fourteen patients with histologically confirmed prostate cancer and five patients with benign prostatic hyperplasia were studied with [¹¹C]choline PET. A mean dose of 430±31 MBq of [¹¹C]choline was injected intravenously and a dynamic emission acquisition of prostate was performed for 30 min. The uptake of [¹¹C]choline was measured as a standardised uptake value (SUV) and as a kinetic influx constant (K _i) obtained from graphical analysis. Both cancerous and hyperplastic prostate were well visualised with [¹¹C]choline against low or moderate tracer accumulation in the bladder and rectal wall. The measured radioactivity in urine was invariably low. In the graphical analysis, linear plots were achieved. The mean K _i of the untreated tumour was 0.205±0.089 min^–1 (range 0.128–0.351; n=7) and the mean SUV was 5.6±3.2 (range 1.9–15.5; n=15). K _i values and SUVs correlated closely (r=0.964, P=0.0005), whereas no correlation could be demonstrated between the tumour uptake of [¹¹C]choline and the histological grade, Gleason score, volume of the prostate or PSA . The mean SUV and the mean K _i of benign hyperplastic prostate were 3.5±1.0 (range 2.0–4.5; n=4) and 0.119±0.076 min^–1 (range 0.065–0.173; n=2). In conclusion, a high uptake of [¹¹C]choline characterises not only carcinomatous but also hyperplastic prostatic tissue. Dynamic imaging of the uptake of [¹¹C]choline in the prostate shows a good applicability of the graphical analysis model with an irreversible compartment. A close correlation between the K _i values and semiquantitative SUVs of tumours supports the use of the simpler SUV in the clinical setting.     

Biodistribution and radiation dosimetry of the norepinephrine transporter radioligand (<Emphasis Type="Italic">S</Emphasis>,<Emphasis Type="Italic">S</Emphasis>)-[<Superscript>18</Superscript>F]FMeNER-D<Subscript>2</Subscript>: a human whole-body PET study

Purpose (S,S)-[¹⁸F]FMeNER-D₂ is a recently developed positron-emission tomography (PET) radioligand for in vivo quantification of the norepinephrine transporter system. The aim of this study was to provide dosimetry estimates for (S,S)-[¹⁸F]FMeNER-D₂ based on human whole-body PET measurements. Methods PET scans were performed for a total of 6.4 h after the injection of 168.9 ± 31.5 MBq of (S,S)-[¹⁸F]FMeNER-D₂ in four healthy male subjects. Volumes of interest were drawn on the coronal images. Estimates of the absorbed dose of radiation were calculated using the OLINDA software. Results Uptake was largest in lungs, followed by liver, bladder, brain and other organs. Peak values of the percent injected dose (%ID) at a time after radioligand injection were calculated for the lung (21.6%ID at 0.3 h), liver (5.1%ID at 0.3 h), bladder (12.2%ID at 6 h) and brain (2.3%ID at 0.3 h). The largest absorbed dose was found in the urinary bladder wall (0.039 mGy/MBq). The calculated effective dose was 0.017 mSv/MBq. Conclusion Based on the distribution and dose estimates, the estimated radiation burden of (S,S)-[¹⁸F]FMeNER-D₂ is lower than that of [¹⁸F]FDG. The radioligand would allow multiple PET examinations in the same research subject per year.     

Imaging the norepinephrine transporter with positron emission tomography: initial human studies with (<Emphasis Type="Italic">S,S</Emphasis>)-[<Superscript>18</Superscript>F]FMeNER-D<Subscript>2</Subscript>

Introduction (S,S)-[¹⁸F]FMeNER-D₂ is a recently developed positron emission tomography (PET) ligand for in vivo quantification of norepinephrine transporter. A monkey occupancy study with the radioligand indicated that (S,S)-[¹⁸F]FMeNER-D₂ can be useful for quantitative PET analysis. In this preliminary study, regional distributions in the living human brain were evaluated. Materials and methods Brain PET measurements were performed for a total of 255 min after the injection of 188.3 ± 5.7 MBq of (S,S)-[¹⁸F]FMeNER-D₂ in four healthy male subjects. Regions of interests were drawn on the thalamus and the caudate in the coregistered MRI/PET images. Results (S,S)-[¹⁸F]FMeNER-D₂ displayed good brain penetration and selective retention in regions rich in norepinephrine reuptake sites. The transient peak equilibrium was reached during the PET measurements. The ratios of radioactivity uptake in the thalamus to that in the caudate were 1.50 ± 0.06 for the time period of 90–255 min. Conclusion The present preliminary investigation indicates that (S,S)-[¹⁸F]FMeNER-D₂ has suitable characteristics for probing the norepinephrine reuptake system with PET in the human brain.     

Two activated stages of microglia and PET imaging of peripheral benzodiazepine receptors with [<Superscript>11</Superscript>C]PK11195 in rats

Objective  

The transition of microglia from the normal resting state to the activated state is associated with an increased expression of peripheral benzodiazepine receptors (PBR). The extent of PBR expression is dependent on the level of microglial activation. A PBR ligand, [¹¹C]PK11195, has been used for imaging of the activation of microglia in vivo. We evaluated whether [¹¹C]PK11195 PET can indicate differences of microglial activation between no treatment and lipopolysaccharide (LPS) treatment in a rat artificial injury model of brain inflammation.     

Targeting murine heart and brain: visualisation conditions for multi-pinhole SPECT with <Superscript>99m</Superscript>Tc- and <Superscript>123</Superscript>I-labelled probes

Purpose  The study serves to optimise conditions for multi-pinhole SPECT small animal imaging of ¹²³I- and ^99mTc-labelled radiopharmaceuticals with different distributions in murine heart and brain and to investigate detection and dose range thresholds for verification of differences in tracer uptake. Methods  A Triad 88/Trionix system with three 6-pinhole collimators was used for investigation of dose requirements for imaging of the dopamine D₂ receptor ligand [¹²³I]IBZM and the cerebral perfusion tracer [^99mTc]HMPAO (1.2–0.4 MBq/g body weight) in healthy mice. The fatty acid [¹²³I]IPPA (0.94 ± 0.05 MBq/g body weight) and the perfusion tracer [^99mTc]sestamibi (3.8 ± 0.45 MBq/g body weight) were applied to cardiomyopathic mice overexpressing the prostaglandin EP₃ receptor. Results  In vivo imaging and in vitro data revealed 45 kBq total cerebral uptake and 201 kBq cardiac uptake as thresholds for visualisation of striatal [¹²³I]IBZM and of cardiac [^99mTc]sestamibi using 100 and 150 s acquisition time, respectively. Alterations of maximal cerebral uptake of [¹²³I]IBZM by >20% (116 kBq) were verified with the prerequisite of 50% striatal of total uptake. The labelling with [^99mTc]sestamibi revealed a 30% lower uptake in cardiomyopathic hearts compared to wild types. [¹²³I]IPPA uptake could be visualised at activity doses of 0.8 MBq/g body weight. Conclusion  Multi-pinhole SPECT enables detection of alterations of the cerebral uptake of ¹²³I- and ^99mTc-labelled tracers in an appropriate dose range in murine models targeting physiological processes in brain and heart. The thresholds of detection for differences in the tracer uptake determined under the conditions of our experiments well reflect distinctions in molar activity and uptake characteristics of the tracers. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

[<Superscript>18</Superscript>F]EF3 is not superior to [<Superscript>18</Superscript>F]FMISO for PET-based hypoxia evaluation as measured in a rat rhabdomyosarcoma tumour model

Purpose  The aim of this investigation was to quantitatively compare the novel positron emission tomography (PET) hypoxia marker 2-(2-nitroimidazol-1-yl)-N-(3[¹⁸F],3,3-trifluoropropyl)acetamide ([¹⁸F]EF3) with the reference hypoxia tracer [¹⁸F]fluoromisonidazole ([¹⁸F]FMISO). Methods  [¹⁸F]EF3 or [¹⁸F]FMISO was injected every 2 days into two separate groups of rats bearing syngeneic rhabdomyosarcoma tumours. In vivo PET analysis was done by drawing regions of interest on the images of selected tissues. The resulting activity data were quantified by the percentage of injected radioactivity per gram tissue (%ID/g) and tumour to blood (T/B) ratio. The spatial distribution of radioactivity was defined by autoradiography on frozen tumour sections. Results  The blood clearance of [¹⁸F]EF3 was faster than that of [¹⁸F]FMISO. The clearance of both tracers was slower in tumour tissue compared with other tissues. This results in increasing T/B ratios as a function of time post tracer injection (p.i.). The maximal [¹⁸F]EF3 tumour uptake, compared to the maximum [¹⁸F]FMISO uptake, was significantly lower at 2 h p.i. but reached similar levels at 4 h p.i. The tumour uptake for both tracers was independent of the tumour volume for all investigated time points. Both tracers showed heterogeneous intra-tumoural distribution. Conclusions  [¹⁸F]EF3 tumour uptake reached similar levels at 4 h p.i. compared with tumour retention observed after injection of [¹⁸F]FMISO at 2 h p.i. Although [¹⁸F]EF3 is a promising non-invasive tracer, it is not superior over [¹⁸F]FMISO for the visualisation of tumour hypoxia. No significant differences between [¹⁸F]EF3 and [¹⁸F]FMISO were observed with regard to the intra-tumoural distribution and the extra-tumoural tissue retention.     

The clinical efficacy of <Superscript>18</Superscript>F-FDG-PET/CT in benign and malignant musculoskeletal tumors

Objective  Most of the current clinical data on the role of 2-[¹⁸F]fluoro-2-deoxy-d-glucose positron emission tomography (¹⁸F-FDG-PET) in musculoskeletal tumors come from patients studied with PET and less frequently with hardware fusion PET/computed tomography (CT). And the number of cases in each report is too small to clarify the exact clinical efficacy of PET or PET/CT. This prompted us to analyze our experience with ¹⁸F-FDG-PET/CT in a relatively large group of patients with musculoskeletal tumors. Methods   ¹⁸F-FDG-PET/CT was performed on 91 patients from May 2004 to June 2007. The final diagnosis was obtained from surgical biopsy in 83 patients (91%) and clinical follow-up in 8 (9%). We analyzed the characteristics and amount of ¹⁸F-FDG uptake in soft tissue and bone tumors, and investigated the ability of ¹⁸F-FDG-PET/CT to differentiate malignant from benign tumors. The cutoff maximum standardized uptake value (SUV_max) was calculated using the receiver-operation characteristic curve method. Sensitivity, specificity, and diagnostic accuracy were calculated with cutoff SUV_max and the final diagnosis. Unpaired t test was used for the statistical analysis. Results  Final diagnosis revealed 19 benign soft tissue tumors (mean SUV_max 4.7), 27 benign bone tumors (5.1), 25 malignant soft tissue tumors (8.8), and 20 malignant bone tumors (10.8). There was a significant difference in SUV_max between benign and malignant musculoskeletal tumors in total (P < 0.002), soft tissue tumors (P < 0.05), and bone tumors (P < 0.02). Sensitivity, specificity, and diagnostic accuracy were 80%, 65.2%, and 73% in total with cutoff SUV_max 3.8, 80%, 68.4%, and 75% in the soft tissue tumors with cutoff SUV_max 3.8, and 80%, 63%, and 70% in the bone tumors with cutoff SUV_max 3.7. Conclusions   ¹⁸F-FDG-PET/CT reliably differentiated malignant soft tissue and bone tumors from benign ones, although there were many false-positive and falsenegative lesions. Further studies with all kinds of musculoskeletal tumors in large numbers are needed to improve the diagnostic accuracy of ¹⁸F-FDG-PET/CT.     

Comparison of the pharmacokinetics of 68Ga-DOTATOC and [18F]FDG in patients with metastatic neuroendocrine tumours scheduled for 90Y-DOTATOC therapy

Purpose The purpose of this study was to evaluate and compare, by means of dynamic PET, the pharmacokinetics of ⁶⁸Ga-DOTATOC, a tracer which reflects the expression of somatostatin receptors (SSTRs), and of [¹⁸F]FDG, a marker of tumour viability, in patients with metastatic neuroendocrine tumours (NETs) in whom ⁹⁰Y-DOTATOC therapy was planned.Materials and methods Fifteen patients (63 lesions) with confirmed metastatic NETs were enrolled in this study. Dynamic [¹⁸F]FDG and ⁶⁸Ga-DOTATOC PET scans were performed on two different days in the same week. The data analysis was based on qualitative and quantitative analysis using a two-tissue compartment model with a blood compartment and a non-compartment model based on the fractal dimension (FD). Multivariate analysis was used for evaluation of the kinetic data.Results Enhanced [¹⁸F]FDG uptake was observed in 43/63 lesions. ⁶⁸Ga-DOTATOC showed pathologically enhanced uptake in all evaluated patients and in 57/63 lesions. Discordant scintigraphic results for [¹⁸F]FDG and ⁶⁸Ga-DOTATOC were observed in 6/15 patients. Global SUV was defined as the SUV measured in the last frame (55–60 min p.i.) of the dynamic series, for each tracer. The median global SUV uptake was 7.9 for ⁶⁸Ga-DOTATOC and 4.6 for [¹⁸F]FDG. The selection of patients for ⁹⁰Y-DOTATOC therapy was based on the uptake of ⁶⁸Ga-DOTATOC. Multiple linear regression analysis was applied to determine the effect of each kinetic parameter (K ₁–k ₄, V _B) on the global SUV of both tracers. The highest positive t-ratio was found for K ₁ (receptor binding), followed by k ₃ (cellular internalisation) and V _B (fractional blood volume), when using the global ⁶⁸Ga-DOTATOC uptake (SUV) as a target variable. Analysis of the [¹⁸F]FDG data revealed the highest positive t-ratio for V _B, followed by k ₃ (phosphorylation) and K ₁ (influx). The comparison of global SUV, K ₁–k ₄ and the FD for [¹⁸F]FDG and ⁶⁸Ga-DOTATOC did not show any statistically significant correlation. The only parameter that demonstrated a significant linear correlation between the tracers was V _B.Conclusion ⁶⁸Ga-DOTATOC is a promising tool for evaluation of the expression of SSTR2 in NETs. The combination of [¹⁸F]FDG and ⁶⁸Ga-DOTATOC dynamic PET studies provides different information regarding the biological properties of lesions in patients with metastatic NETs in whom ⁹⁰Y-DOTATOC therapy is planned. While the global ⁶⁸Ga-DOTATOC uptake is influenced mostly by K ₁, the global [¹⁸F]FDG uptake is mostly influenced by V _B. Only patients with enhanced ⁶⁸Ga-DOTATOC uptake (SUV >5.0) were referred to ⁹⁰Y-DOTATOC therapy.     

Comparison of the biodistribution of two hypoxia markers [<Superscript>18</Superscript>F]FETNIM and [<Superscript>18</Superscript>F]FMISO in an experimental mammary carcinoma

The first aim of this study was to compare the hypoxia imaging ability of fluorine-18 fluoroerythronitroimidazole ([¹⁸F]FETNIM) with that of fluorine-18 fluoromisonimidazole ([¹⁸F]FMISO) in murine tumours of different sizes under two different oxygenation conditions. Secondly, we wanted to assess the biodistribution of the markers in normal tissues under similar conditions. Female CDF1 mice with a C3H mammary carcinoma grown on their backs were used. Tumours were size matched and animals breathed either normal air (21% O₂) or carbogen gas (95% O₂ + 5% CO₂). The gassing procedure was begun 5 min before the intravenous injection of either [¹⁸F]FETNIM or [¹⁸F]FMISO and continued until the mice were sacrificed at 120 min. Blood, tumour, muscle, heart, lung, liver, kidney and fat were removed, counted for radioactivity and weighed. The tumour and muscle were frozen and cut with a cryomicrotome into sections. The spatial distribution of radioactivity from the tissue sections was determined with digital autoradiography. Estimation of the necrotic fraction was made on sections from formalin-fixed tumours. Digital autoradiography showed that the whole tumour-to-muscle radioactivity uptake ratios were significantly higher in normal air-breathing mice than in carbogen-treated mice for both [¹⁸F]FETNIM (4.9±2.6 vs 1.8±0.5; P<0.01) and [¹⁸F]FMISO (4.4±1.0 vs 1.5±0.4; P<0.01). The carbogen treatment had only slight effects on the biodistribution of either marker in normal tissues. The necrotic fraction determined in tumours did not correlate with the tumour volume or with the tumour-to-muscle radioactivity uptake ratio. This study shows that the uptake of both [¹⁸F]FETNIM and [¹⁸F]FMISO correlates with the oxygenation status in tumours. In addition, our data show no significant difference in the intratumoral uptake between the two markers. However, significantly higher radioactivity uptake values were measured for [¹⁸F]FMISO than for [¹⁸F]FETNIM in normal tissues.     

<Superscript>11</Superscript>C-methionine (MET) and <Superscript>18</Superscript>F-fluorothymidine (FLT) PET in patients with newly diagnosed glioma

Purpose  The purpose of this prospective study was to clarify the individual and combined role of l-methyl-¹¹C-methionine-positron emission tomography (MET-PET) and 3′-deoxy-3′-[¹⁸F]fluorothymidine (FLT)-PET in tumor detection, noninvasive grading, and assessment of the cellular proliferation rate in newly diagnosed histologically verified gliomas of different grades. Materials and methods  Forty-one patients with newly diagnosed gliomas were investigated with MET-PET before surgery. Eighteen patients were also examined with FLT-PET. MET and FLT uptakes were assessed by standardized uptake value of the tumor showing the maximum uptake (SUV_max), and the ratio to uptake in the normal brain parenchyma (T/N ratio). All tumors were graded by the WHO grading system using surgical specimens, and the proliferation activity of the tumors were determined by measuring the Ki-67 index obtained by immunohistochemical staining. Results  On semiquantitative analysis, MET exhibited a slightly higher sensitivity (87.8%) in tumor detection than FLT (83.3%), and both tracers were 100% sensitive for malignant gliomas. Low-grade gliomas that were false negative on MET-PET also were false negative on FLT-PET. Although the difference of MET SUV_max and T/N ratio between grades II and IV gliomas was statistically significant (P < 0.001), there was a significant overlap of MET uptake in the tumors. The difference of MET SUV_max and T/N ratio between grades II and III gliomas was not statistically significant. Low-grade gliomas with oligodendroglial components had relatively high MET uptake. The difference of FLT SUV_max and T/N ratio between grades III and IV gliomas was statistically significant (P < 0.01). Again, the difference of FLT SUV_max and T/N ratio between grades II and III gliomas was not statistically significant. Grade III gliomas with non-contrast enhancement on MR images had very low FLT uptake. In 18 patients who underwent PET examination with both tracers, a significant but relatively weak correlation was observed between the individual SUV_max of MET and FLT (r = 0.54, P < 0.05) and T/N ratio of MET and FLT (r = 0.56, P < 0.05). Total FLT uptake in the tumor had a higher correlation (r = 0.89, P < 0.001) with Ki-67 proliferation index than MET uptake (r = 0.49, P < 0.01). Conclusions  PET studies using MET and FLT are useful for tumor detection in newly diagnosed gliomas. However, there is no complimentary information in tumor detection with simultaneous measurements of MET- and FLT-PET in low grade gliomas. FLT-PET seems to be superior than MET-PET in noninvasive tumor grading and assessment of proliferation activity in gliomas of different grades.     

[<Superscript>18</Superscript>F]Fluoroacetate is not a functional analogue of [<Superscript>11</Superscript>C]acetate in normal physiology

Purpose  [¹¹C]Acetate (C-AC) is a general PET tracer of cellular carbon flux and useful for clinical imaging in heart disease as well as prostate cancer and other tumours. C-AC has a high (70%) whole-body extraction fraction, proportional to blood flow in many organs. Trapping is related to organ-specific enzymatic activation and formation of [¹¹C]-acetyl-CoA, the fate of which has been well characterized. Due to the logistic challenges with C-AC, 2-[¹⁸F]fluoroacetate (F-AC) has been proposed as a marker for prostate cancer imaging. Method  We evaluated the potential of F-AC as a tracer for imaging blood flow and early enzymatic steps in the intermediary metabolism. C-AC and F-AC were injected serially in three cynomolgus monkeys and one domestic pig and scanned using PET/CT. A dynamic scan covering heart and liver was followed by repeated whole-body imaging. Kinetic patterns were compared for the myocardium, liver, blood and other organs. Results  C-AC kinetics and organ distribution in both species were similar to those previously established in man. In contrast, F-AC showed prolonged blood retention, no detectable trapping in myocardium or salivary glands, rapid clearance from liver and extensive excretion to bile and urine. Massive defluorination was seen in the pig, resulting in intense skeletal activity. Conclusion  2-[¹⁸F]Fluoroacetate cannot be regarded as a functional analogue of 1-[¹¹C]acetate in normal physiology and appears to be of little use for studies of organ blood flow, intermediary metabolism or lipid synthesis. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

<Superscript>18</Superscript>F-Fluoroglucosylation of peptides,exemplified on <Emphasis Type="Italic">cyclo</Emphasis>(RGDfK)

Purpose  Oxime formation between an aminooxy-functionalized peptide and an ¹⁸F-labelled aldehyde has recently been introduced as a powerful method for the rapid one-step chemoselective synthesis of radiofluorinated peptides. Materials and methods  Here, the potential of using routinely produced and thus readily available [¹⁸F]fluorodeoxyglucose ([¹⁸F]FDG) as the aldehydic prosthetic group was investigated using an aminooxyacetyl-conjugated cyclic RGD peptide (cyclo(RGDfK(Aoa-(Boc)) as a model peptide. Results  The use of [¹⁸F]FDG from routine production ([¹⁸F]FDGTUM) containing an excess of d-glucose did not allow the radiosynthesis of [¹⁸F]FDG-RGD in activities >37 MBq in reasonable yield, rendering the direct use of clinical grade [¹⁸F]FDG for the routine clinical synthesis of ¹⁸F-labelled peptides impossible. Using no-carrier-added (n.c.a.) [¹⁸F]FDG obtained via HPLC separation of [¹⁸F]FDGTUM from excess glucose, however, afforded [¹⁸F]FDG-RGD in yields of 56–93% (decay corrected) and activities up to 37 MBq. Suitable reaction conditions were 20 min at 120°C and pH 2.5, and a peptide concentration of 5 mM. In a preliminary in vivo biodistribution study in M21 melanoma-bearing nude mice, [¹⁸F]FDG-RGD showed increased tumour accumulation compared to the “gold standard” [¹⁸F]galacto-RGD (2.18 vs 1.49 %iD/g, respectively, at 120 min after injection), but also slightly increased uptake in non-target organs, leading to comparable tumour/organ ratios for both compounds. Conclusion  These data demonstrate that chemoselective ¹⁸F-labelling of aminooxy-functionalized peptides using n.c.a. [¹⁸F]FDG represents a radiofluorination/glycosylation strategy that allows preparation of ¹⁸F-labelled peptides in high yield with suitable pharmacokinetics. As soon as the necessary n.c.a. preparation of [¹⁸F]FDG prior to reaction with the Aoa-peptide can be implemented in a fully automated [¹⁸F]FDG-synthesis, [¹⁸F]fluoroglucosylation of peptides may represent a promising alternative to currently used chemoselective one-step ¹⁸F-labelling protocols.