Florian Bretin

Preclinical radiation dosimetry for the novel SV2A radiotracer [18F]UCB-H.

Background[18F]UCB-H was developed as a novel radiotracer with a high affinity for synaptic vesicle protein 2A, the binding site for the antiepileptic levetiracetam. The objectives of this study were to evaluate the radiation dosimetry of [18F]UCB-H in a preclinical trial and to determine the maximum injectable dose according to guidelines for human biomedical research. The radiation dosimetry was derived by organ harvesting and dynamic micro positron emission tomography (PET) imaging in mice, and the results of both methods were compared.MethodsTwenty-four male C57BL-6 mice were injected with 6.96 ± 0.81 MBq of [18F]UCB-H, and the biodistribution was determined by organ harvesting at 2, 5, 10, 30, 60, and 120 min (n = 4 for each time point). Dynamic microPET imaging was performed on five male C57BL-6 mice after the injection of 9.19 ± 3.40 MBq of [18F]UCB-H. A theoretical dynamic bladder model was applied to simulate urinary excretion. Human radiation dose estimates were derived from animal data using the International Commission on Radiological Protection 103 tissue weighting factors.ResultsBased on organ harvesting, the urinary bladder wall, liver and brain received the highest radiation dose with a resulting effective dose of 1.88E-02 mSv/MBq. Based on dynamic imaging an effective dose of 1.86E-02 mSv/MBq was calculated, with the urinary bladder wall and liver (brain was not in the imaging field of view) receiving the highest radiation.ConclusionsThis first preclinical dosimetry study of [18F]UCB-H showed that the tracer meets the standard criteria for radiation exposure in clinical studies. The dose-limiting organ based on US Food and Drug Administration (FDA) and European guidelines was the urinary bladder wall for FDA and the effective dose for Europe with a maximum injectable single dose of approximately 325 MBq was calculated. Although microPET imaging showed significant deviations from organ harvesting, the Pearson’s correlation coefficient between radiation dosimetry derived by either method was 0.9666.

Evaluation of 18F-UCB-H as a Novel PET Tracer for Synaptic Vesicle Protein 2A in the Brain

Synaptic vesicle protein 2 isoforms are critical for proper nervous system function and are involved in vesicle trafficking. The synaptic vesicle protein 2A (SV2A) isoform has been identified as the binding site of the antiepileptic levetiracetam (LEV), making it an interesting therapeutic target for epilepsy. 18F-UCB-H is a novel PET imaging agent with a nanomolar affinity for human SV2A. Methods: Preclinical PET studies were performed with isoflurane-anesthetized rats. The arterial input function was measured with an arteriovenous shunt and a β-microprobe system. 18F-UCB-H was injected intravenously (bolus of 140 ± 20 MBq). Results: Brain uptake of 18F-UCB-H was high, matching the expected homogeneous distribution of SV2A. The distribution volume (Vt) for 18F-UCB-H was calculated with Logan graphic analysis, and the effect of LEV pretreatment on Vt was measured. In control animals the whole-brain Vt was 9.76 ± 0.52 mL/cm3 (mean ± SD; n = 4; test–retest), and the reproducibility in test–retest studies was 10.4% ± 6.5% (mean ± SD). The uptake of 18F-UCB-H was dose dependently blocked by pretreatment with LEV (0.1–100 mg/kg intravenously). Conclusion: Our results indicated that 18F-UCB-H is a suitable radiotracer for the imaging of SV2A in vivo. To our knowledge, this is the first PET tracer for the in vivo quantification of SV2A. The necessary steps for the implementation of 18F-UCB-H production under good manufacturing practice conditions and the first human studies are being planned.

In Vivo PET/CT in a Human Glioblastoma Chicken Chorioallantoic Membrane Model: A New Tool for Oncology and Radiotracer Development

For many years the laboratory mouse has been used as the standard model for in vivo oncology research, particularly in the development of novel PET tracers, but the growth of tumors on chicken chorioallantoic membrane (CAM) provides a more rapid, low cost, and ethically sustainable alternative. For the first time, to our knowledge, we demonstrate the feasibility of in vivo PET and CT imaging in a U87 glioblastoma tumor model on chicken CAM, with the aim of applying this model for screening of novel PET tracers. Methods: U87 glioblastoma cells were implanted on the CAM at day 11 after fertilization and imaged at day 18. A small-animal imaging cell was used to maintain incubation and allow anesthesia using isoflurane. Radiotracers were injected directly into the exposed CAM vasculature. Sodium 18F-fluoride was used to validate the imaging protocol, demonstrating that image-degrading motion can be removed with anesthesia. Tumor glucose metabolism was imaged using 18F-FDG, and tumor protein synthesis was imaged using 2-18F-fluoro-l-tyrosine. Anatomic images were obtained by contrast-enhanced CT, facilitating clear delineation of the tumor, delineation of tracer uptake in tumor versus embryo, and accurate volume measurements. Results: PET imaging of tumor glucose metabolism and protein synthesis was successfully demonstrated in the CAM U87 glioblastoma model. Catheterization of CAM blood vessels facilitated dynamic imaging of glucose metabolism with 18F-FDG and demonstrated the ability to study PET tracer uptake over time in individual tumors, and CT imaging improved the accuracy of tumor volume measurements. Conclusion: We describe the novel application of PET/CT in the CAM tumor model, with optimization of typical imaging protocols. PET imaging in this valuable tumor model could prove particularly useful for rapid, high-throughput screening of novel radiotracers.

Performance Evaluation and X-ray Dose Quantification for Various Scanning Protocols of the GE eXplore 120 Micro-CT

The aim of this paper was to evaluate the performance of the General Electric eXplore 120 micro-CT regarding image quality and delivered dose of several protocols. Image quality (resolution, linearity, uniformity, and geometric accuracy) was assessed using the vmCT phantom developed for the GE eXplore Ultra, the QRM low contrast, and the QRM Bar Pattern Phantom. All dose measurements were performed using a mobileMOSFET dose verification system, and the CTDI100 and the multiple-scan average dose (MSAD) were determined with a custom-built PMMA phantom. Additionally, in vivo scans in sacrificed rats with different weights were acquired to assess dose, contrast, and resolution variation due to X-ray absorption in surrounding tissue. The spatial resolution was determined as between 95 and 138 μm with a geometric accuracy of 0.1%. The system has a highly linear response to the iodine concentrations (0.937-30 mg/ml) for all protocols. The calculated CTDI100 ranged from 20.15 to 56.79 mGy, and the MSAD from 27.98 to 77.45 mGy. The results were confirmed by in vivo scans in rats with different weights, and no impact of body weight on delivered dose could be observed. However, body weight had a slight impact on image contrast and resolution.

X-ray dose quantification for various scanning protocols with the GE eXplore 120 micro-CT

The aim of this study was to quantify the dose delivered by several standard protocols on a GE eXplore 120 micro-CT (Gamma Medica I GE Healthcare) using the computed tomography dose index over 100 mm (CTDI100). Four different protocols with tube voltages of 70 kVp and 80 kVp were investigated by measuring the spatial dose distribution over 100 mm in the axial direction for 9 transaxial positions inside a custom-built cylindrical PMMA phantom. All dose measurements were performed using a mobileMOSFET Dose Verification System (Best Medical Canada, Canada). The axial dose profile of the transaxial center position was used for the CTDl100 calculation. The Fast scan (70 kVp, 0.512 mAs, 192°) delivered a mean dose of 13.92 ± 0.10 mGy, the Fast scan 360 (70 kVp, 0.512 mAs, 360°) 21.24 ± 0.26 mGy, the Soft Tissue Fast scan (70 kVp, 1.6 mAs, 192°) 38.37 ± 0.97 mGy and the Soft Tissue (80 kVp, 0.512 mAs, 192°, step & shoot) 19.63 ± 0.17 mGy. In order to compare the X-ray tube dose output per mAs the CTDI100 of the protocols with 192° were normalized to 360° gantry rotation. At 70 kVp tube voltage the dose output was 45.81 ± 3.92 mGy/mAs across all protocols and 71.89 mGy/mAs at 80 kVp. Protocols with 192° gantry rotation showed inhomogeneity of the dose distribution in the transaxial direction.

Monte Carlo simulations of the dose from imaging with GE eXplore 120 micro-CT using gate

PURPOSE Small animals are increasingly used as translational models in preclinical imaging studies involving microCT, during which the subjects can be exposed to large amounts of radiation. While the radiation levels are generally sublethal, studies have shown that low-level radiation can change physiological parameters in mice. In order to rule out any influence of radiation on the outcome of such experiments, or resulting deterministic effects in the subjects, the levels of radiation involved need to be addressed. The aim of this study was to investigate the radiation dose delivered by the GE eXplore 120 microCT non-invasively using Monte Carlo simulations in GATE and to compare results to previously obtained experimental values. METHODS Tungsten X-ray spectra were simulated at 70, 80, and 97 kVp using an analytical tool and their half-value layers were simulated for spectra validation against experimentally measured values of the physical X-ray tube. A Monte Carlo model of the microCT system was set up and four protocols that are regularly applied to live animal scanning were implemented. The computed tomography dose index (CTDI) inside a PMMA phantom was derived and multiple field of view acquisitions were simulated using the PMMA phantom, a representative mouse and rat. RESULTS Simulated half-value layers agreed with experimentally obtained results within a 7% error window. The CTDI ranged from 20 to 56 mGy and closely matched experimental values. Derived organ doses in mice reached 459 mGy in bones and up to 200 mGy in soft tissue organs using the highest energy protocol. Dose levels in rats were lower due to the increased mass of the animal compared to mice. The uncertainty of all dose simulations was below 14%. CONCLUSIONS Monte Carlo simulations proved a valuable tool to investigate the 3D dose distribution in animals from microCT. Small animals, especially mice (due to their small volume), receive large amounts of radiation from the GE eXplore 120 microCT, which might alter physiological parameters in a longitudinal study setup.

Performance evaluation of the GE eXplore CT 120 micro-CT for various scanning protocols

The aim of this study was to evaluate the performance of the General Electric (GE) eXplore CT 120 microCT using the methodology and image quality assurance vmCT phantom developed for the GE eXplore Ultra. In addition, Quality assurance in Radiology and Medicine (QRM) low contrast and bar pattern phantoms were used. The phantoms were imaged using the six protocols regularly used in our laboratory (Fast scan 220 (PI) or 360 (P2): 70 kV, 32 rnA, 220 or 360 views; Soft tissue fast scan (P3): 70 kV, 50 rnA, 220 views; Soft tissue step & shoot (P4): 80 kV, 32 rnA, 220 views; Low Noise (P5): 100 kV, 50 rnA, 720 views; and In Vivo Bone scan (P6): 100 kV, 50 rnA, 360 views). Data were reconstructed with an isotropic voxel size of 100 μm or 50 μm for detector-binning 4×4 and 2×2, respectively. The Modulation Transfer Function (MTF) obtained with the slanted edge and coil methods agreed very well. A 10% MTF was observed in the range 3.6-4.8 mm-1 (P1&2 = 4.2; P3&4 = 4.8; P5 = 3.6 and P6 = 3.8), corresponding to 95-138 μm resolutions. The smallest bars visually observed on the QRM BarPattern phantom image were 100 μm for all protocols. The geometric accuracy was better than 0.1 %. A highly linear (R2 > 0.999) relationship between measured and expected CT number for both the CT number accuracy and linearity sections of the vmCT phantom was observed with a voltage dependent slope. A cupping effect was observed on the uniform slices. This effect was clearly highlighted by the uniformity-to-noise ratio (PI = 0.58, P2&3&4 = 0.75, P5 = 1.35 and P6 = 2.74) especially for the low-noise protocols P5 and P6. The best contrast discrimination as assessed using the low contrast phantom was observed for P2 and P5 protocols. In conclusion the eXplore CT 120 achieved a resolution in the range 95-138 μm. It was found to be linear and geometrically accurate. The major difference between the protocols was the noise level which limits the detectability of low contrasts.