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Synthesis of 18F Labelled Mini-PEG-RGD Dimer (18F-FPRGD2) and Radiosynthesis and MicroPET Imaging of 2-18F-A-85380

Author: ZhangZuo
Tutor: ZhuLi；WuZhanHong
School: Peking Union Medical College , China
Course: Medical Imaging and Nuclear Medicine
Keywords: N-succinimidyl -4-18F (18F-SFB) Fluorobenzoate 18F-FPRGD2 Synthesis Computer-controlled chemical synthesis module ( , CPCU certification ) 2-18F-A-85380 MicroPET Nicotinic acetylcholine receptor
CLC: R817
Type: Master's thesis
Year: 2008
Downloads: 81
Quote: 0
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Abstract


[Background] positron emission tomography (Positron Emission Tomography, PET) is a positron nuclide ( 11 the C. 18 F 15 O, 13 N) the labeled tracer imaging agent radioactive tracer imaging technology in the diagnosis and therapeutic monitoring of a variety of diseases such as cancer and cardiovascular very important role. Deficiencies existing commonly used positron radionuclide labeled imaging agent (such as 18 the F-FDG, 11 C-Acetic acid, etc.) for the accurate diagnosis of certain tumors people have been committed to the study of a new imaging agent, in order to find new specific imaging agent that can make up for its shortcomings. A PET imaging agent of concern is currently positron labeled biomolecules, including monoclonal antibodies, proteins or small molecules, peptides, etc., the application principle of such imaging agents is the use of a ligand similar radiolabeled things with receptors with high specificity for binding to specific receptors in vivo imaging, wherein the labeled monoclonal antibody, protein, or small molecule polypeptide can be as receptor highly expressed the tissue securely bound ligand. Small molecule synthetic peptide has many advantages, as labeled ligand for imaging, relative protein or monoclonal antibody has a better application prospects. Disintegrin is an important cell surface adhesion molecules, is a group transmembrane glycoprotein, connected by an α chain and a β chain, non-covalent heterodimers, its main effect is mediated by cell-cell and mutual adhesion between cells and the extracellular matrix (ECM) and bi-directional signal transduction, cell adhesion, proliferation, differentiation, metastasis, played an important role in the regulation of apoptosis and play an important role in tumor invasion and metastasis. β integrin α v 3 is one of the important molecules, many studies have shown that with tumor vascular invasion and metastasis. Studies have shown that β , integrin α v 3 mainly through the extracellular matrix (ECM) and RGD tripeptide sequence (arginine - glycine - aspartic acid sequence) of ligand binding role, reported in the literature which can be highly expressed in neovascular endothelial cells, whereas in normal cells express little or lack, therefore, the radioactively labeled RGD peptides can be used as the high specificity of the imaging agent malignancies nuclear medicine imaging, to achieve early diagnosis and treatment purposes. 【Objective】 of existing laboratory SIEMENS / CTI company computer control of chemical synthesis module (CPCU) transformation, for the synthesis of labeled biomolecules auxiliary group N-succinyl imide -4 - 18 F the Fluorobenzoate ( 18 F-SFB). And obtained 18 F-SFB after appropriate treatment for exploratory markers mini-PEG-RGD peptide. [Methods] through the use of double-tube method and the single-tube method to transform the existing CPCU, respectively, in the hot chamber ethyl-4 - trimethylamine benzoate - trifluoromethyl sulfonate reaction precursor synthesis is used to the labeled proteins, antibodies and peptides and other biological molecules 18 F labeled auxiliary group 18 F-SFB products using high performance liquid chromatography (HPLC) to detect and with standard product compared confirmation. The appropriate treatment 18 F-SFB in borate buffer and DMSO as the reaction solvent tag mini-PEG-RGD peptide. [Results] The synthesis of a single-tube method, the total synthesis time of 100 min, after correction obtained intermediate 18 F-FBA yield was 80% ± 5% (n = 4), the final product < sup> 18 F-SFB total decay corrected radiochemical yield of 25% ± 5% of (n = 5); while the dual-tube synthesis, the synthesis process is completed within 80 min, and the mark The method is simple, stable and easy to operate. Correction obtained after the intermediate 18 F-the FBA a yield of 80% ± 5% (n = 4), while the final product after 18 F-SFB total decay corrected the The radiochemical yield of 40% ± 5% (n = 20). In 18 F-FPRGD2 Exploration marking process found that although 18 F-SFB in DMSO as a reaction solvent under the conditions of relatively stable, but was used in this test under the conditions may not be suitable for mini-PEG-RGD peptide tag. Borate buffer as the reaction solvent showed good results, limited laboratory conditions, the product can not be effectively separated the synthesis reaction and product separation conditions to be further optimized. HPLC analysis under the conditions of the test, after a study found 18 F-FPRGD2 the retention time of about 18min. 【Conclusion】 the CPCU semi-automatic synthesis 18 F-SFB method is simple, stable end products detected by HPLC method, the radiochemical purity greater than 99%, which for polypeptide biomolecules future 18 F mark research laid the foundation. In 18 F-FPRGD2 the exploratory markup process, a detailed analysis of the product obtained by the two tagging methods and found that borate buffer solution as a solvent method applicable to the RGD peptide tag . [Background research of the central nervous system receptor imaging is one of the most compelling research direction of molecular nuclear medicine and the field of neurology. Neuronal nicotinic acetylcholine receptors (nAChRs) are a class of ion channel receptors exist in the central nervous tissue of the brain and spinal cord, its concentration can affect cognitive and memory functions of the brain, and Alzheimer's disease (AD), Pa will Sen's disease (PD), epilepsy and other central nervous system disorders and tobacco addiction is closely related to and concern. Receptor imaging agent for positron emission tomography (PET) the receptor imaging technology using isotope labeled specific functions and features of the body for precise positioning of such receptors, nAChRs receptor at the molecular level , help to clarify the mechanism of action of nAChRs related diseases, have an important role in the early diagnosis of the disease and monitoring of treatment efficacy. At present the common clinical 18 F-FDG can not meet the needs of this type of research and clinical applications, the need to develop new specific imaging agents make up 18 F-FDG in this The deficiencies in the areas. 【Objective】 existing SIEMENS / CTI computer-controlled chemical synthesis module (CPCU) imaging agent of transformation, and synthesis of neuronal nicotinic acetylcholine receptors (nAChRs) - 18 FA-85380 resulting product the MicroPET of a normal rat brain imaging studies and to evaluate its effect. [Methods] After the transformation of the existing CPCU, in the hot chamber to Me 3 N -Boc-A-85380.CF 3 SO 3 - body the synthetic the nAChRs imaging agent - 18 FA-85380 products using high performance liquid chromatography (HPLC) detection for reaction ago and were identified by comparison with standard. Appropriate treatment - 18 FA-85380 after rat tail vein injection normal rat the brain MicroPET imaging studies. [Results] Synthesis of 2 - 18 FA-85380 and the total time required for 45 min, and the radiochemical yield was 50% ± 5% (n = 6) in the final product radiochemical purity at 99%, the specific activity of 0.35 ± 0.02 pBq / g. MicroPET imaging study results showed that, 2 - 18 FA-85380 in the rich α 4 β 2 subtype nAChRs hypothalamus in the degree of concentration significantly higher than the surrounding tissue. [Conclusion] modified CPCU synthesis of 2 - 18 FA-85380, method is simple, stable, high specific activity of the product, animal experiments show that basically meet the requirements of clinical imaging.

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