Three-dimensional Monte Carlo-based voxel-wise tumor dosimetry in patients with neuroendocrine tumors who underwent 177Lu-DOTATOC therapy.

BACKGROUND: Patients with advanced neuroendocrine tumors (NETs) of the midgut are suitable candidates for 177Lu-DOTATOC therapy. Integrated SPECT/CT systems have the potential to help improve the accuracy of patient-specific tumor dosimetry. Dose estimations to target organs are generally performed using the Medical Internal Radiation Dose scheme. We present a novel Monte Carlo-based voxel-wise dosimetry approach to determine organ- and tumor-specific total tumor doses (TTD). METHODS: A cohort of 14 patients with histologically confirmed metastasized NETs of the midgut (11 men, 3 women, 62.3 ± 11.0 years of age) underwent a total of 39 cycles of 177Lu-DOTATOC therapy (mean 2.8 cycles, SD ± 1 cycle). After the first cycle of therapy, regions of interest were defined manually on the SPECT/CT images for the kidneys, the spleen, and all 198 tracer-positive tumor lesions in the field of view. Four SPECT images, taken at 4 h, 24 h, 48 h and 72 h after injection of the radiopharmaceutical, were used to determine their effective half-lives in the structures of interest. The absorbed doses were calculated by a three-dimensional dosimetry method based on Monte Carlo simulations. TTD was calculated as the sum of all products of single tumor doses with single tumor volumes divided by the sum of all tumor volumes. RESULTS: The average dose values per cycle were 3.41 ± 1.28 Gy (1.91-6.22 Gy) for the kidneys, 4.40 ± 2.90 Gy (1.14-11.22 Gy) for the spleen, and 9.70 ± 8.96 Gy (1.47-39.49 Gy) for all 177Lu-DOTATOC-positive tumor lesions. Low- and intermediate-grade tumors (G 1-2) absorbed a higher TTD compared to high-grade tumors (G 3) (signed-rank test, p = < 0.05). The pre-therapeutic chromogranin A (CgA) value and the TTD correlated significantly (Pearson correlation: = 0.67, p = 0.01). Higher TTD resulted in a significant decrease of CgA after therapy. CONCLUSION: These results suggest that Monte Carlo-based voxel-wise dosimetry is a very promising tool for predicting the absorbed TTD based on histological and clinical parameters.

Retention efficacy and release of radioiodine in fume hoods.

Procedures to determine the release of hazardous gaseous substances including radioactive iodine are covered by different norms such as the European standard EN 14175 and the German national standard DIN 25466. The detection of sulphur hexafluoride (SF6) is required to comply with the prescribed methodology. The detection limit of this test is 4.5·10-7 mol/m3 in exhaust air. This detection limit would represent a very high activity in the region of 0.27 TBq/m3 leading to an unacceptable risk. We therefore developed a test using a filter system, consisting of a combination of filters capable of separating various chemical forms of airborne radioiodine. Air samples were collected directly in front of the fume hood and in the laboratory beside two different fume hoods of a similar construction with a final activated carbon filter for retention of radioiodine. Particular attention was therefore paid to air samples taken after passage over the filters. Significant differences in the degree of retention of iodine were found between the two fume hoods investigated. In one test a malfunction of the fume hood was demonstrated. In this case 0.148 × 10-3% of the total released activity per m3 air was found 1 cm in front of the hood sash. A remarkably high fraction of the activity released in the fume hood (1.3 × 10-3%/m3 air) was measured after the activated carbon filter. In the ambient air, values of up to 8.6 × 10-6% pro m3 laboratory air sampled were measured, despite a 6-8-fold air exchange. The selected procedure is a factor of 1011 (Schomäcker et al., 2001) more sensitive than the standard recommended methods (EN 14175). The standard test prescribed by the DIN/EN failed to reveal any inadequacy in the protective function of the radionuclide hood with respect to radioiodine retention.

Subtype-selective dopamine receptor radioligands for PET imaging: current status and recent developments.

This review presents a general overview of the subtype-selective dopamine receptor radioligands for in vivo imaging of dopamine receptor expression by positron emission tomography (PET). Besides the (11)C- and (18)F-labeled radioligands which are already in clinical use, a summary of subtype-selective radioligands which had been studied in vitro and in vivo is provided, which shines light onto the current status and recent developments in this field of radiopharmaceutical research.

Synthesis, biological evaluation and radiolabelling by 18F-fluoroarylation of a dopamine D3-selective ligand as prospective imaging probe for PET.

Radical (18)F-fluoroarylation with fluorine-18-labelled arenediazonium chlorides has been successfully applied to the radiochemical synthesis of the dopamine D(3)-selective ligand SH 317 ([(18)F]8). SH 317 has been evaluated as a new PET ligand candidate by in vivo experiments.

Specific accumulation of 18F-deoxyglucose in three-dimensional long-term cultures of human and rodent brain tissue.

AIM: Organotypic slice cultures (OSC) of human brain specimens represent an intriguing experimental model for translational studies addressing, e.g., stem cell transplantation in neurodegenerative diseases or targeting invasion by malignant glioma ex vivo. However, long-term viability and phenomena of structural reorganization of human OSC remain to be further characterized. Here, we report the use of (18)F-deoxyglucose (FDG) for evaluating the viability of brain slice preparations obtained either from postnatal rats or human hippocampal specimens. METHODS: Anatomically well preserved human hippocampi obtained from epilepsy surgery and rat hippocampus slice cultures obtained from six day old Wistar rats were dissected into horizontal slices. The slices were incubated with FDG in phosphate buffered saline up to 1 h, either with or without supplementation of glucose at a concentration of 2.5 mg/ml. Radioactivity within the medium or slice cultures was measured using a gamma-counter. In addition, distribution of radioactivity was autoradiographically visualized and quantified as counts per mm(2). RESULTS: In rat hippocampal slices, FDG accumulated with 1 300 000 +/- 68 000 counts/mm(2), whereas the incorporation of the radioactive label in human slices was in the order of 1 500 000 +/- 370 000 counts/mm(2). The elevation of glucose concentration within the medium led to a significant three-fold decrease of FDG accumulation in rat slices and to a 2.4-fold decrease in human specimens. CONCLUSIONS: FDG accumulated in organotypic brain cultures of human or rodent origin. FDG is thus suited to investigate the viability of OSC. Furthermore, these preparations open new ways to study the factors governing cerebral FDG uptake in brain tissue ex vivo.

Tissue distribution of radioiodinated FAUC113: assessment of a pyrazolo(1,5-a) pyridine based dopamine D4 receptor radioligand candidate.

AIM: Disturbances of the D4 receptor subtype have been implicated in the genesis of a broad range of psychiatric disorders. In order to assess the suitability of a radioiodinated analogue of the D4-selective ligand FAUC 113 for tracer studies in vivo, we investigated the in-vivo stability, biodistribution and brain-uptake of 7-(131)I-FAUC 113 in Sprague-Dawley rats. METHODS: Radiolabelling was carried out with high radiochemical yield and specific activity. After intravenous injection, blood and tissue samples, taken at designated time intervals, were collected for analysis. Analyses of metabolites were performed by radio-hplc and radio-tlc. For in-vivo evaluation, sagittal cryo-sections of the rat brain were investigated by in-vitro and ex-vivo autoradiography on a mu-Imager system. RESULTS: 7-(131)I-FAUC 113 was rapidly cleared from blood. Highest uptake was observed in kidney (0.603 +/- 0.047% ID/g, n = 4) and liver (0.357 +/- 0.070% ID/g, n = 4) at 10 min p.i.; 7-(131)I-FAUC 113 displayed rapid uptake (0.21-0.26% ID/g) and fast clearance in various brain regions consistent with the determined logP-value of 2.36 +/- 0.15 (n = 4). In-vivo stability of 7-(131)I-FAUC 113 was confirmed in the frontal cortex (>95%). Ex-vivo autoradiography revealed a frontal cortex-to-cerebellum ratio of 1.57 +/- 0.13 at 10 min p.i. (n = 6). Coinjection with L-750667 could not suppress any putative specific binding of 7-(131)I-FAUC 113. In-vitro autoradiography using authentic 7-iodo-FAUC 113 or L-750667 failed to cause significant displacement of the radioligand. CONCLUSIONS: Radioiodinated FAUC 113 does not allow imaging of D4 receptors in the rat brain in vivo nor in vitro. Further work should aim at the development of selective dopamine D4 radioligands with improved tracer characteristics, such as receptor affinity and subtype selectivity, specific activity or blood-brain barrier permeability.

Influence of TSH on uptake of [18F]fluorodeoxyglucose in human thyroid cells in vitro.

Recent clinical evidence suggests that positron emission tomography with fluorine-18 fluorodeoxyglucose (FDG-PET) is more accurate in detecting thyroid carcinomatous tissue at high than at low TSH levels. The aim of this study was to determine the influence of TSH on FDG uptake in human thyroid cells in vitro. Monolayers of human thyroid tissue were cultured after mechanical disintegration and enzymatic digestion of samples from patients undergoing surgery for nodular goitre. The purity of thyroid cell preparations was ascertained by immunohistochemical staining for the epithelial antigen KL-1, and their viability by measuring the synthesis of thyroglobulin in vitro. The cells were incubated with 0.8-1.5 MBq FDG/ml uptake medium for 1 h. FDG uptake in thyroid cells was quantified as percent of whole FDG activity per well (% ID) or as % ID in relation to total protein mass. This experimental protocol was subsequently varied to study the effect of incubation time, glucose dependency and TSH. Furthermore, radio-thin layer chromatography was used to identify intracellular FDG metabolites. FDG accumulated in the thyroid cells linearly with time, doubling roughly every 20 min. Uptake was competitively inhibited by unlabelled glucose and decreased to approximately 70% at 100 mg/dl glucose compared to the value measured in glucose-free medium. FDG was intracellularly trapped as FDG-6 phosphate and FDG-1,6-diphosphate. TSH significantly increased FDG uptake in vitro in a time- and concentration-dependent manner: Cells cultured at a TSH concentration of 50 micro U/ ml doubled FDG uptake compared to TSH-free conditions, and uptake after 72 h of TSH pre-incubation was approximately 300% of that without TSH pre-incubation. TSH stimulates FDG uptake by benign thyroid cells in a time- and concentration-dependent manner. This supports the clinical evidence that in well-differentiated thyroid carcinomas, most of which are still TSH-sensitive, FDG-PET is more accurate at high levels of TSH.