The Radiopharmaceutical Synthesis Of GABA_A/BZ Receptor PET Tracer¹¹C-FMZ And Its Evaluation Of Cerebral Neuronal Loss Of Severe Traumatic Brain Injury Patients

Part1:The radiopharmaceutical synthesis, identification and quality control of GABAA/BZ receptor PET tracer11C-FMZPurpose:To study the method of radiopharmaceutical synthesis of GABAA/BZ receptor PET tracer11C-FMZ, and to implement its identification and quality control. Methods:1mg precursor of11C-FMZ(desmethylflumazenil) was methylated and labeled with11C using11C triflate methane in the room temperature condition. The fluid was then diluted into11C-FMZ ethanol-water solution and was identified with HPLC and the quality control was carried out. Results:11C-FMZ injection was colorless pure transparent fluid. HPLC identification showed that it was the same material as FMZ standard substance. pH value, radiochemical purification, specific activity and biological identification results accord with the PET radiopharmaceutical requirements. Conclusion:GABAA/BZ receptor PET tracer11C-FMZ can be obtained by labeling desmethylflumazeriil with positron nuclide11C. The production,11C-FMZ injection, was identified to be qualified to human research purposes.Part2:The establishment of the methodology of11C-FMZ neurotransmitter receptor imagingPurpose:To study the methodology of neurotransmitter imaging of GABAA/BZ receptor PET tracer11C-FMZ, and try to establish the standard acquisition and reconstruction protocols and normal control database of11C-FMZ PET. Methods:9normal controls were scanned by CT and0-60min post-injection list mode PET. The PET data were reconstructed staticly from30to40min and dynamically from0to60min using17frames. The static SUVmean CRR, dynamic peak frames, frame-wise SUVmean, CRR variance, BP and the variance coefficient of SUVmean CRR and BP using different reference tissues were calculated. Results:The main uptake of11C-FMZ is in the cerebral and cerebellar cortices, with the visual cortex of the occipital lobe most obvious. The static SUVmean CRR of the major brain regions vary from5.71±1.50to7.44±1.80. BP vary from2.51±0.91to3.83±1.18. The peak frames vary from4.14±0.9(approximately1.5to2min) to10.14±0.9(approximately10to12.5min). The variances of SUVmean CRR of the major brain regions in the stable period vary from0.11+0.02to0.27+0.14. The variance coefficients of global SUVmean CRR are0.40±0.06(right white matter)、0.34±0.09(left white matter)and0.17±0.08(pons). The variance coefficients of global BP are0.36±0.18(right white matter),0.34±0.17(left white matter) and0.14±0.08(pons). Conclusion:The neurotransmitter receptor imaging of11C-FMZ PET is feasible. The concentration of the radiopharmaceutical was elevated rapidly in all brain regions after injection. The radiopharmaceuticals are washed out swiftly in reference tissues while the cortical binding results slow cleaning. The thalami and cerebella stay between the reference tissues and the cortices. The pons is more suitable for quantification of SUVmean CRR and BP than semiovale white matter.Part3The evaluation of cerebral neuron loss of severe traumatic brain injury patients using11C-FMZ PET.Purpose:To compare the variances of the important parameters of major brain regions between normal control and traumatic brain injury patients. Methods:9normal controls and4severe traumatic brain injury patients were scanned using the same protocols as in Part2. The important parameters were calculated and compared between the controls and patients. Results:The static SUVmean CRR, dynamic peak frames, frame-wise SUVmean CRR variance, BP and the variance coefficient of SUVmean CRR and BP using different reference tissues were calculated. Results:The TBI patients’ main uptake of11C-FMZ is in the cortices, however significantly lower than normal controls’, with the severely injured lateral more obvious. The static SUVmean CRR of the major brain regions vary from3.18±1.42to5.1±2.7. BP vary from2.31±0.65to3.17±0.39, which are significantly lower than those of the normal controls’, the p value<0.05. The peak frames vary from4.5±0.58(approximately1.5to2min) to10±0.82 (approximately10to12.5min), which are inordinately earlier or later than those of the normal controls’. The variances of SUVmean CRR of the major brain regions in the stable period vary from0.1±0.06to0.2±0.03. The variance coefficients of global SUVmean CRR are0.36±0.15(mildly injured white matter) and0.16±0.03(pons) The variance coefficients of global BP are0.35±0.15(mildly injured white matter) and0.13±0.07(pons). The pons is still significantly lower than the white matter, p value<0.05. Conclusion:"C-FMZ PET is a safe and effective method to evaluate neuron loss. The cortical neuronal density of the TBI patients is significantly lower than that of the normal controls. The SUVmean CRRs fluctuate stably in the period of30-40min post-injection, and this time period can function as an imaging diagnostic window.11C-FMZ PET is helpful to preliminary severity judgment and prognosis by observing neuronal reservation.