Geant4 simulations of proton beam transport through a carbon or beryllium degrader and following a beam line.

Monte Carlo simulations based on the Geant4 simulation toolkit were performed for the carbon wedge degrader used in the beam line at the Center of Proton Therapy of the Paul Scherrer Institute (PSI). The simulations are part of the beam line studies for the development and understanding of the GANTRY2 and OPTIS2 treatment facilities at PSI, but can also be applied to other beam lines. The simulated stopping power, momentum distributions at the degrader exit and beam line transmission have been compared to accurate benchmark measurements. Because the beam transport through magnetic elements is not easily modeled using Geant4a connection to the TURTLE beam line simulation program was made. After adjusting the mean ionization potential of the carbon degrader material from 78 eV to 95 eV, we found an accurate match between simulations and benchmark measurements, so that the simulation model could be validated. We found that the degrader does not completely erase the initial beam phase space even at low degraded beam energies. Using the validation results, we present a study of the usability of beryllium as a degrader material (mean ionization potential 63.7 eV). We found an improvement in the transmission of 30-45%, depending on the degraded beam energy, the higher value for the lower energies.

Cerebral 6-[18F]fluoro-L-DOPA uptake in rhesus monkey: pharmacological influence of aromatic amino acid decarboxylase (AAAD) and catechol-O-methyltransferase (COMT) inhibition.

FDOPA/PET scans were performed in one rhesus monkey to study the influence of three catechol-O-methyltransferase (COMT) inhibitors (CGP 28014, OR-611 and Ro 40-7592) on FDOPA pharmacokinetics. COMT inhibitors were administered in combination with carbidopa, a peripherally acting inhibitor of the aromatic amino acid decarboxylase (AAAD). FDOPA was administered intravenously and its metabolic fate in plasma was determined using an HPLC system with an on-line gamma-gamma coincidence detector. Cerebral tracer uptake was assessed in the striatum and in a non-dopaminergic brain region (occipital cortex). In the periphery, the pharmacokinetic efficiency of FDOPA was increased due to the combined inhibition of COMT and AAAD activity. All three COMT inhibitors reduced the FDOPA methylation rate constant in plasma, with complete suppression obtained in the case of Ro 40-7592. In the brain, specific 18F radioactivity (striatal minus brain reference radioactivity) increased as a result of the increase in FDOPA plasma availability following the administration of COMT and AAAD inhibitors. We established a significant linear correlation between striatal radioactivity and FDOPA plasma levels (r = 0.924 +/- 0.048, P < 0.0001 for total striatal and r = 0.948 +/- 0.054, P < 0.0001 for specific striatal radioactivity). Using plasma FDOPA radioactivity as input, we found that the striatal FDOPA uptake rate constant KiFD was not changed by any of the inhibitors. Thus, the enhancement of striatal radioactivity after application of enzyme inhibitors is a consequence of the increase in plasma FDOPA that becomes available for conversion to fluorodopamine in the striatal dopaminergic nerve terminals. By contrast, using the radioactivity in a non-dopaminergic region (cortex) as input, we found that the striatal FDOPA uptake rate constant Ki(ref) was significantly (P < 0.0001) increased following pretreatment with COMT inhibitors. Our analysis demonstrated that Ki(ref) and the 3-OMFD contribution to the cerebral radioactivity were inversely correlated.

Positron emission tomography in drug evaluation: influence of three different catechol-O-methyltransferase inhibitors on metabolism of [NCA] 6-[18F]fluoro-L-dopa in rhesus monkey.

We compared the influence of three different catechol-O-methyltransferase (COMT) inhibitors (CGP 28014, OR-611 and Ro 40-7592) on the metabolism of no-carrier-added (NCA) 6-[18F]fluoro-L-dopa (6-FDOPA) in one Rhesus monkey. All three COMT inhibitors improved 6-FDOPA availability in plasma, increased the specific uptake in the brain and thus improved 6-FDOPA uptake measurements using positron emission tomography (PET). Best results were obtained with Ro 40-7592.

Gallium-67/gallium-68-[DFO]-octreotide--a potential radiopharmaceutical for PET imaging of somatostatin receptor-positive tumors: synthesis and radiolabeling in vitro and preliminary in vivo studies.

UNLABELLED: When labeled with gamma-emitting radionuclides, somatostatin analogs have the potential to localize somatostatin receptor-positive tumors using gamma camera scintigraphy. We present a somatostatin analog, [DFO]-octreotide (SDZ 216-927), that comprises desferrioxamine B coupled to octreotide via a succinyl linker. This conjugate can be labeled with either 67Ga for gamma scintigraphy or 68Ga for PET imaging. The 67Ga-labeled conjugate is stable in vitro to autoradiolysis over a 24-hr period. METHODS: Rats bearing a somatostatin receptor-positive pancreatic islet cell tumor were injected with 20 MBq of 67Ga[DFO]-octreotide (33 GBq 67Ga/mumole). RESULTS: After 1 hr, the accumulation of 67Ga[DFO]-octreotide was 0.38 +/- 0.08 %ID/g and the tumor-to-nontumor ratios for blood, muscle, liver and intestine were 2.5, 7.4, 1.9 and 1.6, respectively. PET studies with 68Ga[DFO]-octreotide recorded a very rapid accumulation at the tumor and a subsequent residence half-life of about 6 hr. CONCLUSION: Gallium-68-[DFO]-octreotide can be used in PET studies to diagnose receptor-positive tumors such as gastroenteropancreatic, small-cell lung and breast tumors.

Modification of in vitro mouse embryogenesis by X-rays and fluorochromes.

In view of planned studies using single particle irradiation at the Institute for Medical Radiobiology (IMR), confocal microscopy will become an important tool to visualise subtle changes in embryo morphology. Therefore, the influence of X-rays and that of three different fluorochromes on the in vitro development of murine 2-cell stage embryos was investigated. Embryos of B6C3F1 mice were cultured at 32 h post-conception (pc) and treated with X-rays, acridine orange (AO), ethidium bromide (EB) or propidium iodide (PI), respectively, in various doses (0.0-3.0 Gy) or concentrations (AO: 0.05-2.00 micrograms/ml; EB and PI: 0.50-10.00 micrograms/ml). Additional experiments using combinations of AO and irradiation were performed. The embryos were cultivated for a total of 7 days and checked for their vital status by morphological endpoints such as the percentage of embryos that reached the blastocyst stage and the hatching rate. After treatment of the 2-cell embryos with AO, EB and PI, the dose-effect curves with the endpoint 'hatching rate' showed a 23-fold reduction of the ED50 for AO (0.23 microgram/ml) compared with EB (5.30 micrograms/ml). Despite the higher toxicity, AO had much better staining qualities in subtoxic concentrations than EB. PI showed no toxicity in these experiments and was used as an inverse control for embryo vitality. No synergistic modification of the radiogenic effects could be seen in combination experiments (AO+X-rays).

Radioimmuno positron emission tomography with monoclonal antibodies: a new approach to quantifying in vivo tumour concentration and biodistribution for radioimmunotherapy.

Radioimmunodetection of tumours with monoclonal antibodies is becoming an established procedure. Positron emission tomography (PET) shows better resolution than normal gamma camera single photon emission tomography and can provide more precise quantitative data. Thus, in the present study, these powerful methods have been combined to perform radioimmuno PET (RI-PET). Monoclonal antibodies directed against carcinoembryonic antigen (CEA) an IgG, its F(ab')2 and a mouse-human chimeric IgG derived from it were labelled with 124I, a positron-emitting radionuclide with a convenient physical half-life of four days. Mice, xenografted with a CEA-producing human colon carcinoma, were injected with the 124I-MAb and the tumours were visualized using PET. The concentrations of 124I in tumour and normal tissue were determined by both PET and direct radioactivity counting of the dissected animals, with very good agreement. To allow PET quantification, a procedure was established to account for the presence of radioactivity during the absorption correction measurement (transmission scan). Comparison of PET and tissue counting indicates that this novel combination of radioimmunolocalization and PET (RI-PET) will provide, in addition to more precise diagnosis, more accurate radiation dosimetry for radioimmunotherapy.

Sensitivity evaluation of positron emission tomographs.

Applying the recommended guidelines of the Instrumentation Group of the EEC Concerted Action, the sensitivity of an ECAT 933/4-16 scanner was determined. Several filters were used to reconstruct the images. On the images regions of interest (ROIs) were defined, and the ROI-counts were compared to the specific activity in the phantom. Whereas the uncorrected sensitivity was not influenced by the reconstruction filters, the sensitivity corrected for the scatter fraction appeared to be dependent on the reconstruction filter. Images reconstructed with a non-smoothing filter (Ramp filter, Shepp filter) yielded a higher sensitivity due to the lower reconstructed scatter fraction.

Study on the stability of the calibration and normalization in PET and the influence of drifts on the accuracy of quantification.

With regard to the quality control of quantification in positron emission tomography some characteristics were examined, to develop a simple method for frequent monitoring. The stability and uniformity of the detector count rate was checked by plotting the RMS deviation of the non normalized count rate and the standard deviation of the normalized count rate, each normalized to its value after the calibration or normalization respectively. Switching off a single detector did not impair the image quality, but the normalized image pixel counts were reduced by 2%-3% when a detector block was switched off. Thus in case of need, a weak detector can still be used to perform a scan. A reduced count rate capability at specific activities above 5 x 10(4) Bq/ml (approximately 1.5 x 10(5) corrected true system counts/s or approximately 1.5 x 10(4)/s for a plane) was found compared to the maximum usable activity of 8 x 10(4) Bq/ml obtained 1 year earlier, indicating a drift in the count loss corrections. A variation of the room temperature changes the temperature distribution inside the gantry by 5% per degree C and the drift of the sensitivity (normalized image pixel counts) is 2% per degree C.