Synthesis And Evaluation Of Two ¹⁸F-labeled Aromatic Amino Acids For Tumor PET Imaging

Objective:The limitations of[¹⁸F]fluorodeoxyglucose(¹⁸F]FDG),like producing false-positive or-negative results,low image contrast in brain tumor diagnosis and poor differentiation of tumor and inflammatory,necessitate the development of amino acid based radiopharmaceuticals.In the present study,two kinds of ¹⁸F-labeled aromatic amino acids,[¹⁸F]FDGly-NHPhe and 3-O-(2-[¹⁸F]fluoroethyl)-L-DOPA([¹⁸F]FEDOPA),were designed and synthesized by two different ¹⁸F labeling methods.Methods:[¹⁸F]FEDOPA was prepared from a direct nucleophilic substitution with ¹⁸F using the new precusor,N-?tert-butoxycarbonyl?-3-?3-?2-?tosyloxy?ethoxy?-4-?tert-butoxycarbonyloxy??-L-DOPA methyl ester.The ¹⁸F-fluorinated intermediate was purified via semi-preparative HPLC and hydrolyzed by 4 mol/L HCl.After neutralized with 2 mol/L NaOH,[¹⁸F]FEDOPA was obtained as injectable solution.The bio-distribution studie was performed on healthy ICR mice.Micro-PET/CT imaging was performed and compared with[¹⁸F]FDG on S180-H22 tumor-bearing ICR mice.[¹⁸F]FDGly-NH-Phewaspreparedbycondensing[¹⁸F]FDGwith L-4-aminophenylalanine in an acidic condition,and purifying with semi-preparative-high performance liquid chromatography?HPLC?.Synthesis of the reference compound([¹⁹F]FDGly-NH-Phe)wasachievedbyincubationof[¹⁹F]FDGwith L-4-aminophenylalanine in the presence of acetic acid,and the structure was determined by the nuclear magnetism and mass spectrometry.The metabolism studies was performed and compared with[¹⁸F]FDG on S180 tumor-bearing ICR mice.Results:The overall radiochemical yield of[¹⁸F]FEDOPA was 33±6%?n=10,decay corrected?within 90 min of radiosynthesis time,and the specific activity was 55GBq/?mol.The radiochemical purity of[¹⁸F]FEDOPA?at room temperature?at 0,60,120 and 240 min were 99.35%,98.58%,97.98%and 97.49%,respectively,which indicated the high in vitro stability.Biodistribution study in healthy ICR mice showed rapid clearance of[¹⁸F]FEDOPA from kidneys and low uptake in most tissues especially in brain and heart.The radioactivity in brain and heart at 60 min post-injection of[¹⁸F]FEDOPA were 1.01±0.18 and 0.90±0.24%ID/g,respectively.And there was no obvious uptake change in bone over the 90 minutes.Micro-PET/CT imaging showed high accumulation of[¹⁸F]FEDOPA in tumor tissue.Furthermore,the ratios of tumor to brain and tumor to heart for[¹⁸F]FEDOPA?H22/brain:7.73±2.10,S180/brain:4.62±1.52,H22/heart:4.33±1.22,S180/heart:2.59±0.30?were higher than those of[¹⁸F]FDG?H22/brain:2.14±0.71,S180/brain:2.14±0.71,H22/heart:1.89±0.25,S180/heart:1.56±0.30?at 60 min post-injection.For radio-synthesis of[¹⁸F]FDGly-NH-Phe,the coupling of[¹⁸F]FDG and L-4-aminophenylalanine was achieved with a decay-uncorrected yields?79.8±13.5%,n=10?within 50 min.The radiochemical purity of[¹⁸F]FDGly-NH-Phe was greater than99%according to the analytical HPLC.The specific activity?SA?was estimated to be over than 37 GBq/?mol.The identity of the radiolabeled compound was confirmed by co-injection with the reference compound[¹⁹F]FDGly-NH-Phe.Metabolism studies indicated that the high in vivo stability?in plasma and urine?of[¹⁸F]FDGly-NH-Phe,and the decomposition into[¹⁸F]FDG in the acidic tumor microenvironment.Conclusion:All these results indicated that[¹⁸F]FEDOPA and[¹⁸F]FDGly-NH-Phe,as two kinds of ¹⁸F-labeled aromatic amino acids,would be potential amino acid tracers for tumor PET imaging.