Automated synthesis and preliminary evaluation of [18F]FDPA for cardiac inflammation imaging in rats after myocardial infarction

Tiantian Mou,Jing Tian,Xiang Li,Wei Dong,Xia Lu,Hongzhi Mi,Mingkai Yun,Ziwei Zhu,Junqi Li,Yi Tian,Xiaoli Zhang

doi:10.1038/s41598-020-75705-2

Abstract

A translocator protein 18 kDa targeted radiotracer, N,N-diethyl-2-(2-(4-[18F]fluorophenyl)-5,7-dimethylpyrazolo[1,5-a] pyrimidin-3-yl) acetamide ([18F]FDPA), was automated synthetized and evaluated for cardiac inflammation imaging. Various reaction conditions for an automated synthesis were systematically optimized. MicroPET/CT imaging were performed on normal rats and rats with myocardial infarction (MI). Normalized SUV ratios of [18F]FDPA to [13N]NH3 (NSRs) in different regions were calculated to normalize the uptake of [18F]FDPA to perfusion. The amount of TBAOMs and the volume/proportion of water were crucial for synthesis. After optimization, the total synthesis time was 68 min. The non-decay corrected radiochemical yields (RCYs) and molar activities were 19.9 ± 1.7% and 169.7 ± 46.5 GBq/μmol, respectively. In normal rats, [18F]FDPA showed a high and stable cardiac uptake and fast clearance from other organs. In MI rats, NSRs in the peri-infarct and infarct regions, which were infiltrated with massive inflammatory cells revealed by pathology, were higher than that in the remote region (1.20 ± 0.01 and 1.08 ± 0.10 vs. 0.89 ± 0.05, respectively). [18F]FDPA was automated synthesized with high RCYs and molar activities. It showed a high uptake in inflammation regions and offered a wide time window for cardiac imaging, indicating it could be a potential cardiac inflammation imaging agent.

Highlights

Iodaneyl)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)-N,N-diethylacetamide TBAOMs Tetrabutylammonium methanesulfonate PK11195 1-(2-Chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide solid phase extraction (SPE) Solid phase extraction NH4Ac Ammonium acetate tR Retention time radiochemical purity (RCP) Radiochemical purity myocardial infarction (MI) Myocardial infarction standardized uptake values (SUVs) Standardized uptake value Normalized SUV ratios of [18F]FDPA to [13N]NH3 (NSRs) Normalized SUV ratio of [ 18F]FDPA to [ 13N]NH3
Several studies reported that Translocator protein kDa (TSPO) Positron emission tomography (PET) imaging could assess cardiac inflammation, such as myocarditis[13,14] and inflammation after ischemia[15], making it a “hot target” for cardiac inflammation imaging
When the temperature increased to 120 °C, or the reaction time extended to 20 min, RCC reduced dramatically

Summary

Introduction

Iodaneyl)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)-N,N-diethylacetamide TBAOMs Tetrabutylammonium methanesulfonate PK11195 1-(2-Chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide SPE Solid phase extraction NH4Ac Ammonium acetate tR Retention time RCP Radiochemical purity MI Myocardial infarction SUV Standardized uptake value NSR Normalized SUV ratio of [ 18F]FDPA to [ 13N]NH3. Translocator protein 18 kDa (TSPO) is mainly localized in the outer mitochondrial membrane It is associated with various biological processes such as controlling the translocation of cholesterol, regulating mitochondrial membrane potential, mediating immune response, modulating voltage dependent calcium channels and apoptosis[1]. Since it is overexpressed in the activated microglia, the TSPO targeted imaging was focused on evaluating neuroinflammation in the past, including Alzheimer’s disease, Parkinson’s disease and dementia[2,3,4]. It might be used to monitor inflammatory response, facilitating physicians to choose the appropriate patients and right time for intervention. We optimized an automated synthesis of [18F]FDPA based on the previously reported spirocyclic iodonium ylide m ethod[19], and were first to evaluate [18F]FDPA for myocardial inflammation imaging

Methods

Results

Discussion

Conclusion