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. 18 F-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. 18 F-UCB-H was injected intravenously (bolus of 140 ± 20 MBq). Results: Brain uptake of 18 F-UCB-H was high, matching the expected homogeneous distribution of SV2A. The distribution volume (V t ) for 18 F-UCB-H was calculated with Logan graphic analysis, and the effect of LEV pretreatment on V t was measured. In control animals the whole-brain V t was 9.76 ± 0.52 mL/cm 3 (mean ± SD; n 5 4; test-retest), and the reproducibility in test-retest studies was 10.4% ± 6.5% (mean ± SD). The uptake of 18 F-UCB-H was dose dependently blocked by pretreatment with LEV (0.1-100 mg/kg intravenously). Conclusion: Our results indicated that 18 F-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 18 F-UCB-H production under good manufacturing practice conditions and the first human studies are being planned.
This first human dosimetry study of [(18)F]UCB-H indicated that the tracer shows similar radiation burdens to widely used common clinical tracers. Single injections of at maximum 672 MBq for US practice and 649 MBq for European practice keep radiation exposure below recommended limits. Recently published preclinical dosimetry data extrapolated from mice provided satisfactory prediction of total body and effective dose but showed significant differences in organ absorbed doses compared to human data.
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 18 F-fluoride was used to validate the imaging protocol, demonstrating that image-degrading motion can be removed with anesthesia. Tumor glucose metabolism was imaged using 18 F-FDG, and tumor protein synthesis was imaged using 2-18 F-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 18 F-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. PETi maging has proved an indispensable tool in oncology research and in clinical oncology (1). 18 F-FDG has been widely used to study tumor proliferation and metastasis in vivo, and radiotracers targeting specific proteins expressed on tumor cells are constantly under development (2). In recent years, there has been a substantial growth in the use of combined PET and CT imaging, both in the clinic and for small-animal research. This combination yields functional imaging data with useful anatomic information.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. However, despite their wide use in oncology research, mouse models obviously require all usual aspects of animal husbandry, necessitating cost and taking up valuable lab space. In particular, rodent models can be limited in their usefulness by difficulty in obtaining exact measures of tumor progression (such as volume) (3). Ethical issues relating to animal suffering and public opinion are also of increasing concern (4). Clearly, an alternative could be useful.The chicken chorioallantoic membra...
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.
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 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 m 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 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.
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