CT-based SPECT attenuation correction and assessment of infarct size: results from a cardiac phantom study.

RATIONALE: Myocardial perfusion SPECT is a commonly performed, well established, clinically useful procedure for the management of patients with coronary artery disease. However, the attenuation of photons from myocardium impacts the quantification of infarct sizes. CT-Attenuation Correction (AC) potentially resolves this problem. This contention was investigated by analyzing various parameters for infarct size delineation in a cardiac phantom model. METHODS: A thorax phantom with a left ventricle (LV), fillable defects, lungs, spine and liver was used. The defects were combined to simulate 6 infarct sizes (5-20% LV). The LV walls were filled with 100120 kBq/ml 99mTc and the liver with 10-12 kBq/ml 99mTc. The defects were filled with water of 50% LV activity to simulate transmural and non-transmural infarction, respectively. Imaging of the phantom was repeated for each configuration in a SPECT/CT system. The defects were positioned in the anterior as well as in the inferior wall. Data were acquired in two modes: 32 views, 30 s/view, 180° and 64 views, 15 s/view, 360° orbit. Images were reconstructed iteratively with scatter correction and resolution recovery. Polar maps were generated and defect sizes were calculated with variable thresholds (40-60%, in 5% steps). The threshold yielding the best correlation and the lowest mean deviation from the true extents was considered optimal. RESULTS: AC data showed accurate estimation of transmural defect extents with an optimal threshold of 50% [non attenuation correction (NAC): 40%]. For the simulation of non-transmural defects, a threshold of 55% for AC was found to yield the best results (NAC: 45%). The variability in defect size due to the location (anterior versus inferior) of the defect was reduced by 50% when using AC data indicating the benefit from using AC. No difference in the optimal threshold was observed between the different orbits. CONCLUSION: Cardiac SPECT/CT shows an improved capability for quantitative defect size assessment in phantom studies due to the positive effects of attenuation correction.

WWSSF - a worldwide study on radioisotopic renal split function: reproducibility of renal split function assessment in children.

PURPOSE: The split or differential renal function is the most widely accepted quantitative parameter derived from radionuclide renography. To examine the intercenter variance of this parameter, we designed a worldwide round robin test. METHODS: Five selected dynamic renal studies have been distributed all over the world by e-mail. Three of these studies are anonymized patient data acquired using the EANM standardized protocol and two studies are phantom studies. In a simple form, individual participants were asked to measure renal split function as well as to provide additional information such as data analysis software, positioning of background region of interest, or the method of calculation. RESULTS: We received the evaluation forms from 34 centers located in 21 countries. The analysis of the round robin test yielded an overall z-score of 0.3 (a z-score below 1 reflecting a good result). However, the z-scores from several centers were unacceptably high, with values greater than 3. In particular, the studies with impaired renal function showed a wide variance. CONCLUSION: A wide variance in the split renal function was found in patients with impaired kidney function. This study indicates the ultimate importance of quality control and standardization of the measurement of the split renal function. It is especially important with respect to the commonly accepted threshold for significant change in split renal function by 10%.

Multiparametric PET imaging in thyroid malignancy characterizing tumour heterogeneity: somatostatin receptors and glucose metabolism.

PURPOSE: Radiolabelled somatostatin (SST) analogues have proven useful in diagnosing tumours positive for SST receptor (SSTR). As different subtypes of SSTR are expressed on the tumour cell surface, the choice of appropriate therapeutic SST analogue is crucial. We evaluated the SSTR status of thyroid cancer patients who had signs of progressive disease comparing different SSTR ligands for PET imaging to evaluate possible further therapeutic options. METHODS: PET with (68)Ga-radiolabelled SSTR ligands DOTA lanreotide (DOTA-LAN), DOTA-Tyr(3) octreotide (DOTA-TOC) and (18)F-FDG was performed in 31 patients with thyroid cancer (TC). These 31 patients comprised 18 with radioiodine non-avid differentiated TC (DTC) including 6 papillary TC (PTC), 8 follicular TC (FTC) and 4 oxyphilic TC (oxyTC), 5 with anaplastic TC (ATC), and 8 with medullary TC (MTC). The PET results were compared in a region-based evaluation. RESULTS: All patients underwent a PET study with (68)Ga-DOTA-LAN, 28 patients with (68)Ga-DOTA-TOC and 28 patients with (18)F-FDG. A lack of SSTR expression was found in 13 of the 31 patients (42%) with negative results with both SSTR tracers in 12 patients. Ambiguous results with both SSTR tracers were observed in one patient. High tracer uptake in SSTR PET images was seen in seven DTC patients (39%; two PTC, three FTC, two oxyTC), in four ATC patients (80%) and in six MTC patients (75%). Lesions showing aerobic glycolysis on (18)F-FDG PET were found in 24 of 28 patients (86%) with corresponding positive results with (68)Ga-DOTA-LAN in 35% and with (68)Ga-DOTA-TOC in 29%. CONCLUSION: The heterogeneous SSTR profile of TC tumour lesions needs to be evaluated using different SSTR PET tracers to characterize more closely the SSTR subtype affinities in patients with progressive TC in order to further stratify therapy with SSTR therapeutics.

Stereotactic radiofrequency ablation of unresectable intrahepatic cholangiocarcinomas: a retrospective study.

PURPOSE: To evaluate treatment effects, complications, and outcome of percutaneous stereotactic radiofrequency ablation (SRFA) of intrahepatic cholangiocarcinoma (ICC). PATIENTS AND METHODS: Eleven consecutive patients (nine men and two women) with a total of 36 inoperable ICCs (18 initial lesions, 16 lesions newly detected during follow-up, and two local recurrences) underwent SRFA between December 2004 and June 2010. Two different radiofrequency ablation (RFA) devices with internally cooled electrodes were used. Tumor diameters ranged from 0.5 to 10 cm (median 3.0 cm). A total of 23 SRFA sessions were performed. The efficacy of SRFA was evaluated by contrast-enhanced computed tomography or magnetic resonance imaging 1 month after treatment and then every 3 months. RESULTS: Primary technical effectiveness rate was 92%. Further follow-up every 3 months revealed three local recurrences (8%), two of which were successfully retreated, resulting in a secondary technical effectiveness rate of 98%. After a total of 23 RFA sessions, three major complications occurred (13%) that could be managed interventionally. Mean follow-up time was 35 months (range 12-81 months). One- and 3-year overall survival rates were 91 and 71%, respectively. The median overall survival was 60 months (according to the life table method). Eight (73%) of 11 patients were still alive at the end of follow-up. CONCLUSION: SRFA is effective in the treatment of unresectable ICC even if the tumor is large and located close to major vessels. SRFA shows a survival benefit compared to other palliative treatment options and may also be considered as the first-line local treatment of ICCs in selected patients.

PET based volume segmentation with emphasis on the iterative TrueX algorithm.

PURPOSE: To assess the influence of reconstruction algorithms for positron emission tomography (PET) based volume quantification. The specifically detected activity in the threshold defined volume was investigated for different reconstruction algorithms as a function of volume size and signal to background ratio (SBR), especially for volumes smaller than 1ml. Special attention was given to the Siemens specific iterative reconstruction algorithm TrueX. METHODS: Measurements were performed with a modified in-house produced IEC body phantom on a Siemens Biograph 64 True Point PET/CT scanner (Siemens, Medical Systems) for six different SBRs (2.1, 3.8, 4.9, 6.7, 8.9, 9.4 and without active background (BG)). The phantom consisted of a water-filled cavity with built-in plastic spheres (0.27, 0.52, 1.15, 2.57, 5.58 and 11.49ml). The following reconstruction algorithms available on the Siemens Syngo workstation were evaluated: Iterative OSEM (OSEM) (4 iterations, 21 subsets), iterative TrueX (TrueX) (4 iterations, 21 subsets) and filtered backprojection (FBP). For the threshold based volume segmentation the software Rover (ABX, Dresden) was used. RESULTS: For spheres larger than 2.5ml a constant threshold (standard deviation (SD) 10%) level was found for a given SBR and reconstruction algorithm and therefore a mean threshold for the largest three spheres was calculated. This threshold could be approximated by a function inversely proportional to the SBR. The threshold decreased with increasing SBR for all sphere sizes. For the OSEM algorithm the threshold for small spheres with 0.27, 0.52 and 1.15ml varied between 17% and 44% (depending on sphere size). The threshold for the TrueX algorithm was substantially lower (up to 17%) than for the OSEM algorithm for all sphere sizes. The maximum activity in a specific volume yielded the true activity for the OSEM algorithm when using a SBR independent correction factor C, which depended on sphere size. For the largest three volumes a constant factor C=1.10±0.03 was found. For smaller volumes, C increased exponentially due to the partial volume effect. For the TrueX algorithm the maximum activity overestimated the true activity. CONCLUSION: The threshold values for PET based target volume segmentation increased with increasing sphere size for all tested algorithms. True activity values of spheres in the phantom could be extracted using experimentally determined correction factors C. The TrueX algorithm has to be used carefully for quantitative comparison (e.g. follow-up) and multicenter studies.

68Ga-siderophores for PET imaging of invasive pulmonary aspergillosis: proof of principle.

UNLABELLED: The diagnosis of invasive pulmonary aspergillosis (IPA) is difficult and lacks specificity and sensitivity. In the pathophysiology of Aspergillus fumigatus, iron plays an essential role as a nutrient during infection. A. fumigatus uses a specific and highly efficient iron uptake mechanism based on iron-complexing ferric ion Fe(III) siderophores, which are a requirement for A. fumigatus virulence. We aimed to evaluate the potential of siderophores radiolabeled with (68)Ga, a positron emitter with complexing properties comparable to those of Fe(III), as a radiopharmaceutical for imaging IPA. METHODS: (68)Ga radiolabeling of the A. fumigatus siderophores desferri-triacetylfusarinine C (TAFC) and desferri-ferricrocin (FC) was performed at high specific activity. Stability, protein binding, and log P values were determined. In vitro uptake in A. fumigatus cultures was tested under varying conditions. Biodistribution was studied in healthy noninfected BALB/c mice, and uptake was studied in a model of A. fumigatus infection using immunosuppressed Lewis rats. RESULTS: High-specific-activity (68)Ga labeling could be achieved, and resulting complexes were stable in serum, toward diethylenetriaminepentaacetic acid and Fe(III) challenge. Both siderophores showed hydrophilic properties ((68)Ga-TAFC, log P = -2.59; (68)Ga-FC, log P = -3.17) with low values of protein binding for (68)Ga-TAFC (<2%). Uptake of both siderophores was highly dependent on the mycelial iron load and could be blocked with an excess (10 microM) of siderophore or NaN(3), indicating specific, energy-dependent uptake. In noninfected mice, (68)Ga-TAFC showed rapid renal excretion and low blood values (1.6 +/- 0.37 percentage injected dose per gram [%ID/g] at 30 min); in urine only intact (68)Ga-TAFC was detected. In contrast, (68)Ga-FC revealed high retention in blood (16.1 +/- 1.07 %ID/g at 90 min) and rapid metabolism. In the rat IPA model, lung uptake of (68)Ga-TAFC was dependent on the severity of infection, with less than 0.04 %ID/g in control rats (n = 5) and 0.29 +/- 0.11 %ID/g in mildly infected (n = 3) and 0.95 +/- 0.37 %ID/g in severely infected (n = 4) rats. PET showed focal accumulation in infected lung tissue. CONCLUSION: Both siderophores bound (68)Ga with high affinity, and (68)Ga-TAFC, especially, showed high stability. (68)Ga-TAFC displayed highly selective accumulation by A. fumigatus subspecies in vitro and in vivo. The high and specific uptake by A. fumigatus proves the potential of (68)Ga-labeled siderophores for the specific detection of A. fumigatus during infection. They hold promise as new PET agents for IPA.

Response of recurrent high-grade glioma to treatment with (90)Y-DOTATOC.

UNLABELLED: The treatment of patients with high-grade malignant glioma still represents an unsolved clinical problem. We report the treatment of 3 patients who had World Health Organization grade IV recurrent glioblastoma: a 23-y-old woman and 2 men aged 61 and 62 y. METHODS: All 3 patients were treated with the somatostatin receptor radiopharmaceutical (90)Y-labeled [1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid(0)-d-Phe(1),Tyr(3)]octreotide (DOTATOC). A cumulated dose of 1.7-2.2 GBq given in 3 or 4 cycles was locally injected into a previously implanted catheter system. RESULTS: Treatment was successful in all 3 patients, with only minor side effects reported. After treatment, MRI and PET showed complete remission in one patient and partial remission in the other patients. These findings correlated well with clinical improvement and improved quality of life. CONCLUSION: Receptor-mediated radionuclide therapy by locally injected (90)Y-DOTATOC is feasible and well tolerated. This approach represents an attractive strategy for the treatment of locally recurring or progressing glioblastoma.

Radiolabeling of lipid-based nanoparticles for diagnostics and therapeutic applications: a comparison using different radiometals.

Radiolabeling of nanoparticles (NPs) has been performed for a variety of reasons, such as for studying pharmacokinetics, for imaging, or for therapy. Here, we describe the in vitro and in vivo evaluation of DTPA-derivatized lipid-based NP (DTPA-NP) radiolabeled with different radiometals, including (111)In and (99m)Tc, for single-photon emission computed tomography (SPECT), (68)Ga for positron emission tomography (PET), and (177)Lu for therapeutic applications. PEGylated DTPA-NP with varying DTPA amounts, different composition, and size were radiolabeled with (111)In, (177)Lu, and (68)Ga, using various buffers. (99m)Tc-labeling was performed directly and by using the carbonyl aquaion, [(99m)Tc(H(2)O)(3)(CO)(3)](+). Stability was tested and biodistribution evaluated. High labeling yields (>90%) were achieved for all radionuclides and different liposomal formulations. Specific activities (SAs) were highest for (111)In (>4 MBq/mug liposome), followed by (68)Ga and (177)Lu; for (99m)Tc, high labeling yields and SA were only achieved by using [(99m)Tc(H(2)O)(3)(CO)(3)](+). Stability toward DTPA/histidine and in serum was high (>80 % RCP, 24 hours postpreparation).). Biodistribution in Lewis rats revealed no significant differences between NP in terms of DTPA loading and particle composition; however, different uptake patterns were found between the radionuclides used. We observed lower retention in blood (<3.3 %ID/g) and lower liver uptake (< 2.7 %ID/g) for (99m)Tc- and (68)Ga, compared to (111)In-NP (blood, <4 %ID/g; liver, <3.6 %ID/g). Imaging potential was shown by both PET magnetic resonance imaging fusion imaging and SPECT imaging. Overall, our study shows that PEGylated DTPA-NP are suitable for radiolabeling studies with a variety of radiometals, thereby achieving high SA suitable for targeting applications.

68Ga-DOTA-Tyr3-octreotide PET for assessing response to somatostatin-receptor-mediated radionuclide therapy.

UNLABELLED: (68)Ga-labeled 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-d-Phe(1)-Tyr(3)-octreotide (DOTA-TOC) PET has proven its usefulness in the diagnosis of patients with neuroendocrine tumors. Radionuclide therapy ((90)Y-DOTA-TOC or (177)Lu-DOTA-octreotate) is a choice of treatment that also requires an accurate diagnostic modality for early evaluation of treatment response. Our study compared (68)Ga-DOTA-TOC PET with CT or MRI using the Response Evaluation Criteria in Solid Tumors. Furthermore, standardized uptake values (SUVs) were calculated and compared with treatment outcome. METHODS: Forty-six patients (29 men, 17 women; age range, 34-84 y) with advanced neuroendocrine tumors were investigated before and after 2-7 cycles of radionuclide therapy. Long-acting somatostatin analogs were not applied for at least 6 wk preceding the follow-up. Data were acquired with a dedicated PET scanner. Emission image sets were acquired at 90-100 min after injection. (68)Ga-DOTA-TOC PET images were visually interpreted by 2 experienced nuclear medicine physicians. For comparison, multislice helical CT scans and 1.5-T MRI scans were obtained. Attenuation-corrected PET images were used to determine SUVs. Repeated CT evaluation and other imaging modalities, for example, (18)F-FDG, were used as the reference standard. RESULTS: According to the reference standard, (68)Ga-DOTA-TOC PET and CT showed a concordant result in 32 patients (70%). In the remaining 14 patients (30%), discrepancies were observed, with a final outcome of progressive disease in 9 patients and remission in 5 patients. (68)Ga-DOTA-TOC PET was correct in 10 patients (21.7%), including 5 patients with progressive disease. In these patients, metastatic spread was detected with the follow-up whole-body PET but was missed when concomitant CT was used. On the other hand, CT confirmed small pulmonary metastases not detected on (68)Ga-DOTA-TOC in 1 patient and progressive liver disease not detected on (68)Ga-DOTA-TOC in 3 patients. Quantitative SUV analysis of individual tumor lesions showed a large range of variability. CONCLUSION: (68)Ga-DOTA-TOC PET shows no advantage over conventional anatomic imaging for assessing response to therapy when all CT information obtained during follow-up is compared. Only the development of new metastases during therapy was detected earlier in some cases when whole-body PET was used. SUV analysis of individual lesions is of no additional value in predicting individual responses to therapy.

Bone metastases in patients with neuroendocrine tumor: 68Ga-DOTA-Tyr3-octreotide PET in comparison to CT and bone scintigraphy.

UNLABELLED: Somatostatin receptor scintigraphy is an accurate imaging modality for the diagnosis of neuroendocrine tumor. Because detection of distant metastases has a major impact on treatment, early diagnosis of metastatic spread is of great importance. So far, no standard procedure has become established for the early diagnosis of bone metastases from neuroendocrine tumor. We compared the diagnostic value of CT with that of the novel somatostatin analog (68)Ga-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-d-Phe(1)-Tyr(3)-octreotide ((68)Ga-DOTATOC) in the detection of such metastases. METHODS: Fifty-one patients (22 women and 29 men; age range, 32-87 y) with histologically verified neuroendocrine tumor were included in this study. PET scans were fused with CT scans using a vacuum fixation device. (18)F-NaF or (99m)Tc-dicarboxypropane diphosphonate bone scans or clinical follow-up served as the reference standard. RESULTS: Twelve of the 51 patients had no evidence of bone metastases on any of the available imaging modalities, and 37 patients had (68)Ga-DOTATOC PET results true-positive for bone metastases. (68)Ga-DOTATOC PET results were true-negative for 12 patients, false-positive for one, and false-negative for another, resulting in a sensitivity of 97% and a specificity of 92%. (68)Ga-DOTATOC PET detected bone metastases at a significantly higher rate than did CT (P < 0.001). Furthermore, conventional bone scans confirmed the results of somatostatin receptor PET but did not reveal additional tumors in any patients. CONCLUSION: (68)Ga-DOTATOC PET is a reliable, novel method for the early detection of bone metastases in patients with neuroendocrine tumor. Our results show that CT and conventional bone scintigraphy are less accurate than (68)Ga-DOTATOC PET in the primary staging or restaging of neuroendocrine tumor.

68Ga-DOTA-Tyr3-octreotide PET in neuroendocrine tumors: comparison with somatostatin receptor scintigraphy and CT.

UNLABELLED: The aim of this study was to evaluate the diagnostic value of a new somatostatin analog, (68)Ga-labeled 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-d-Phe(1)-Tyr(3)-octreotide ((68)Ga-DOTA-TOC), for PET in patients with known or suspected neuroendocrine tumors. PET was compared with conventional scintigraphy and dedicated CT. METHODS: Eighty-four patients (48 men, 36 women; age range, 28-79 y; mean age +/- SD, 58.2 +/- 12.2 y) were prospectively studied. For analysis, patients were divided into 3 groups: detection of unknown primary tumor in the presence of clinical or biochemical suspicion of neuroendocrine malignancy (n = 13 patients), initial tumor staging (n = 36 patients), and follow-up after therapy (n = 35 patients). Each patient received 100-150 MBq (68)Ga-DOTA-TOC. Imaging results of PET were compared with (99m)Tc-labeled hydrazinonicotinyl-Tyr(3)-octreotide ((99m)Tc-HYNIC-TOC) and (111)In-DOTA-TOC. CT was also performed on every patient using a multidetector scanner. Each imaging modality was interpreted separately by observers who were unaware of imaging findings before comparison with PET. The gold standard for defining true-positive (TP), true-negative (TN), false-positive (FP), and false-negative (FN) results was based on all available histologic, imaging, and follow-up findings. RESULTS: PET was TP in 69 patients, TN in 12 patients, FP in 1 patient, and FN in 2 patients, indicating a sensitivity of 97%, a specificity of 92%, and an accuracy of 96%. The FP finding was caused by enhanced tracer accumulation in the pancreatic head, and the FN results were obtained in patients with a tumor of the gastrointestinal tract displaying liver metastases. (68)Ga-DOTA-TOC showed higher diagnostic efficacy compared with SPECT (TP in 37 patients, TN in 12 patients, FP in 1 patient, and FN in 34 patients) and diagnostic CT (TP in 41 patients, TN in 12 patients, FP in 5 patients, and FN in 26 patients). This difference was of statistical significance (P < 0.001). However, the combined use of PET and CT showed the highest overall accuracy. CONCLUSION: (68)Ga-DOTA-TOC PET shows a significantly higher detection rate compared with conventional somatostatin receptor scintigraphy and diagnostic CT with clinical impact in a considerable number of patients.

[Evaluation of the performance of a gamma camera equipped with a 5/8" versus 1" thick NaI detector]. / Vergleich der Abbildungseigenschaften einer Gammakamera mit 5/8" (15 mm) NaI-Szintillationskristall und 1" (25 mm)-Kristall.

The upgrade of a gamma camera from a 5/8" to a 1" thick crystal, the latter with StarBrite technology, prompted to the investigation of changes in performance parameters for planar scintigraphy and SPECT as well as for PET in coincidence mode. For planar and SPECT parameters, the performance was measured according to NEMA Standard Protocol NU1-2001. No changes were found in terms of intrinsic uniformity, intrinsic spatial resolution, linearity, energy resolution, system resolution, and tomographic system resolution. The only change was an increase of system sensitivity for higher energy gamma rays. For the PET scanner in coincidence mode, the image quality of the camera was determined according to NEMA NU2-2001. Visually and in terms of contrast values there was a significant improvement of image quality. Changes in image quality relevant for clinical use were tested by evaluation of planar patient scans acquired within a short time with two gamma cameras of the same type, different only in crystal thickness (5/8" and 1"). No statistically significant difference was found between corresponding scans. For planar and SPECT imaging, the gamma camera with 1" thick detector and StarBrite technology demonstrated the same performance of a camera with a 5/8" crystal. For PET in coincidence mode the new detector proved clearly superior.

11C-acetate positron emission tomography imaging and image fusion with computed tomography and magnetic resonance imaging in patients with recurrent prostate cancer.

PURPOSE: To assess the clinical value of computed tomography (CT) and magnetic resonance imaging (MRI) image fusion with 11C-acetate (AC) positron emission tomography (PET) imaging for detection and exact location of clinically occult recurrences. PATIENTS AND METHODS: Fifty prostate cancer patients with elevated/increasing serum prostate-specific antigen levels after radical therapy underwent whole-body AC PET. Uptake was initially interpreted as normal, abnormal, or equivocal. In case of abnormal or equivocal uptake, additional conventional imaging techniques, such as CT, MRI, and bone scans, were performed. To precisely define the anatomic location of abnormal uptake and to improve characterization of equivocal lesions, a software-assisted image fusion (CT-PET, MRI-PET) was performed and evaluated as site-by-site analysis of 51 abnormal (n = 37) or equivocal (n = 14) sites of all 50 patients. In 17 patients, additional histopathologic evaluation was available. RESULTS: In five (10%), 13 (26%), and 32 (64%) of the 50 patients, AC PET studies demonstrated AC uptake judged as normal, equivocal, and abnormal, respectively. Image fusion changed characterization of equivocal lesions as normal in five (10%) of 51 sites and abnormal in nine (18%) of 51 sites. It precisely defined the anatomic location of abnormal uptake in 37 (73%) of 51 sites. AC PET findings did influence patient management in 14 (28%) of 50 patients. CONCLUSION: Retrospective fusion of AC PET and CT/MRI is feasible and seems to be essential for final diagnosis. This is particularly true in patients with AC uptake in the prostate region.

Combined PET and microdialysis for in vivo assessment of intracellular drug pharmacokinetics in humans.

UNLABELLED: Because many drugs possess an intracellular site of action, the knowledge of intracellular concentration-time profiles is desirable. In the present study, PET, which measures total (i.e., intracellular, extracellular, and intravascular) concentrations of radiolabeled drugs in tissue, and microdialysis, which determines unbound drug concentrations in the extracellular space fluid of tissue, were combined to describe the intracellular pharmacokinetics of a model compound--that is, the (18)F-labeled antibiotic (18)F-ciprofloxacin--in vivo in humans. METHODS: Ten healthy male volunteers received a mixture of 687 +/- 50 MBq of (18)F-ciprofloxacin and 200 mg of unlabeled ciprofloxacin as an intravenous bolus infusion over 10 min. The pharmacokinetics of ciprofloxacin in skeletal muscle tissue were assessed by means of combined PET and in vivo microdialysis for 5 h after drug administration. A 3-compartment pharmacokinetic model was fitted to the tissue concentration-time profiles of ciprofloxacin measured by PET to estimate the rate constants of ciprofloxacin uptake and transport. RESULTS: In muscle tissue, mean total and extracellular peak concentration (C(max)) values of ciprofloxacin of 1.8 +/- 0.4 microg/mL and 0.7 +/- 0.2 microg/mL were attained at 95 +/- 34 min and 48 +/- 20 min after drug administration, respectively. The extracellular-to-intracellular exchange appeared to be very fast, with an estimated rate constant k(3) of 1.69 +/- 0.25 min(-1). An intracellular-to-extracellular concentration ratio (C(intra)/C(extra)) of 3.2 +/- 0.8 was reached at 110 min after injection and followed by sustained intracellular retention of the antibiotic for the remainder of the experiment. The predicted extracellular concentration-time profiles from the compartmental modeling were in good agreement with the measured microdialysis data. CONCLUSION: The results obtained in the present study were in accordance with previous in vitro data describing cellular ciprofloxacin uptake and retention. The presently used PET/microdialysis combination might be useful during research and development of new drugs, for which knowledge of intracellular concentrations is of interest.

Influence of functional haplotypes in the drug transporter gene ABCB1 on central nervous system drug distribution in humans.

BACKGROUND AND OBJECTIVE: Single nucleotide polymorphisms in the human multidrug-resistance gene ABCB1 have been reported to be associated with altered expression and function of P-glycoprotein, an efflux transporter, expressed at the blood-brain barrier. To test whether certain ABCB1 haplotypes contribute to interindividual differences in central nervous system drug distribution, brain distribution of a model P-glycoprotein substrate, the calcium channel inhibitor verapamil, was measured by positron emission tomography (PET) in 2 groups of healthy volunteers. METHODS: Ten homozygous carriers (cases) of the TTT haplotype (3435T, 1236T, and 2677T) and 10 controls homozygous for the wild-type CGC haplotype (3435C, 2677G, and 1236C) were administered a mean intravenous bolus of 412 +/- 114 MBq carbon 11-labeled verapamil containing less than 15 nmol of unlabeled verapamil. PET imaging of brain tissue and venous blood sampling were performed for 1 hour after dosing. RESULTS: As a measure of brain penetration, the ratio of PET area under the time-radioactivity curve (AUC) to plasma AUC was calculated from time-radioactivity curves, with a mean ratio of 1.1 +/- 0.3 (SD) (95% confidence interval, 0.9-1.3) for cases and 1.1 +/- 0.2 (95% confidence interval, 0.9-1.2) for controls, respectively (P = .96). Mean brain AUC values were 31.2 +/- 3.9 and 35.7 +/- 5.7 for the TTT and CGC haplotype, respectively (P = .11). Plasma AUCs were not significantly different. CONCLUSION: No difference in the brain distribution of [(11)C]verapamil could be detected in healthy volunteers differing in ABCB1 haplotypes.

An inter-laboratory comparison study of image quality of PET scanners using the NEMA NU 2-2001 procedure for assessment of image quality.

An inter-laboratory comparison study was conducted to assess the image quality of PET scanners in Austria. The survey included both dedicated PET scanners (D-PET, n = 8) and coincidence cameras (GC-PET, n = 7). Measurement of image quality was based on the NEMA (National Electrical Manufacturers Association) NU 2-2001 protocol and the IEC (International Electrotechnical Commission) body phantom. The latter contains six fillable spheres ranging in diameter from 37 mm down to 10 mm and a 'lung' insert. The two largest lesions L1-2 simulate cold lesions, the four smaller ones (L3-6) are filled with 18F and activity concentration ratios relative to background of 8:1 and 4:1, respectively. Acquisition and reconstruction in the study employed the participating institutes' standard oncological processing protocol. Calculation of contrast of the spheres was performed with a fully automated procedure. Contrast quality indices (CQIs) reflecting global performance were obtained by summing individual contrast values. Other image quality parameters calculated according to the NEMA protocol were background variability and relative error for correction of attenuation and scatter. Contrast values obtained were 61 +/- 16 and 37 +/- 14 for L1 (per cent contrast +/- SD for D-PET and GC-PET, respectively), 57 +/- 16 and 29 +/- 16 for L2, 46 +/- 10 and 26 +/- 6.3 for L3, 37 +/- 10 and 15 +/- 4.3 for L4, 26 +/- 11.5 and 6.1 +/- 2.5 for L5, 14 +/- 7.1 and 2.6 +/- 2.6 for L6, with D-PET systems consistently being superior to GC-PET systems. CQIs permitted ranking of the scanners, also demonstrating a clear distinction between D-PET and GC-PET systems. Background variability was largest for GC-PET systems; the relative error of attenuation and scatter correction was significantly correlated with image quality for D-PET systems only. The study demonstrated considerable differences in image quality not only between GC-PET and D-PET systems but also between individual D-PET systems with possible consequences for clinical interpretation of images and measurement of quantitative indices such as the standardized uptake value. The study provided valuable feedback to the participants as well as baseline data for improving interchangeability of PET images and of quantitative indices between different laboratories.

In vitro and in vivo evaluation of [18F]ciprofloxacin for the imaging of bacterial infections with PET.

PURPOSE: The suitability of the 18F-labelled fluoroquinolone antibiotic ciprofloxacin ([18F]ciprofloxacin) for imaging of bacterial infections with positron emission tomography (PET) was assessed in vitro and in vivo. METHODS: For the in vitro experiments, suspensions of various E. coli strains were incubated with different concentrations of [18F]ciprofloxacin (0.01-5.0 microg/ml) and radioactivity retention was measured in a gamma counter. For the in vivo experiments, 725 +/- 9 MBq [18F]ciprofloxacin was injected intravenously into four patients with microbiologically proven bacterial soft tissue infections of the lower extremities and time-radioactivity curves were recorded in infected and uninfected tissue for 5 h after tracer injection. RESULTS: Binding of [18F]ciprofloxacin to bacterial cells was rapid, non-saturable and readily reversible. Moreover, bacterial binding of the agent was similar in ciprofloxacin-resistant and ciprofloxacin-susceptible clinical isolates. These findings suggest that non-specific binding rather than specific binding to bacterial type II topoisomerase enzymes is the predominant mechanism of bacterial retention of the radiotracer. PET studies in the four patients with microbiologically proven bacterial soft tissue infections demonstrated locally increased radioactivity uptake in infected tissue, with peak ratios between infected and uninfected tissue ranging from 1.8 to 5.5. Radioactivity was not retained in infected tissue and appeared to wash out with a similar elimination half-life as in uninfected tissue, suggesting that the kinetics of [18F]ciprofloxacin in infected tissue are governed by increased blood flow and vascular permeability due to local infection rather than by a binding process. CONCLUSION: Taken together, our results indicate that [18F]ciprofloxacin is not suited as a bacteria-specific infection imaging agent for PET.

[18F]Ciprofloxacin, a new positron emission tomography tracer for noninvasive assessment of the tissue distribution and pharmacokinetics of ciprofloxacin in humans.

The biodistribution and pharmacokinetics of the fluorine-18-labeled fluoroquinolone antibiotic [(18)F]ciprofloxacin in tissue were studied noninvasively in humans by means of positron emission tomography (PET). Special attention was paid to characterizing the distribution of [(18)F]ciprofloxacin to select target tissues. Healthy volunteers (n = 12) were orally pretreated for 5 days with therapeutic doses of unlabeled ciprofloxacin. On day 6, subjects received a tracer dose (mean injected amount, 700 +/- 55 MBq, which contained about 0.6 mg of unlabeled ciprofloxacin) of [(18)F]ciprofloxacin as an intravenous bolus. Thereafter, PET imaging and venous blood sampling were initiated. Time-radioactivity curves were measured for liver, kidney, lung, heart, spleen, skeletal muscle, and brain tissues for up to 6 h after radiotracer administration. The first application of [(18)F]ciprofloxacin in humans has demonstrated the safety and utility of the newly developed radiotracer for pharmacokinetic PET imaging of the tissue ciprofloxacin distribution. Two different tissue compartments of radiotracer distribution could be identified. The first compartment including the kidney, heart, and spleen, from which the radiotracer was washed out relatively quickly (half-lives [t(1/2)s], 68, 57, and 106 min, respectively). The second compartment comprised liver, muscle, and lung tissue, which displayed prolonged radiotracer retention (t(1/2), >130 min). The highest concentrations of radioactivity were measured in the liver and kidney, the main organs of excretion (standardized uptake values [SUVs], 4.9 +/- 1.0 and 9.9 +/- 4.4, respectively). The brain radioactivity concentrations were very low (<1 kBq. g(-1)) and could therefore not be quantified. Transformation of SUVs into absolute concentrations (in micrograms per milliliter) allowed us to relate the concentrations at the target site to the susceptibilities of bacterial pathogens. In this way, the frequent use of ciprofloxacin for the treatment of a variety of infections could be corroborated.