Al ¹⁸F-NOTA-Folate:a Novel PET Radiotracer For Folate Receptor Targeting

ObjectiveHighly expression of the folate receptor (FR) in various cancer types offers FR a promising target for imaging and therapy of cancer using folate-based radiopharmaceuticals. Over the last decade, there has been growing interest in the 18F labeled folic acid and its analogues in the study of FR positive tumor targeting diagnosis. Herein, we report the synthesis and evaluation of a novel Al18F-NOTA-Folate tracer using "one pot" reaction suitable for positron emission tomography(PET).MethodsAl18F-NOTA-Folate tracer was synthesized using "one pot" reaction approach. The labeling conditions of A118F-NOTA-Folate tracer, hydrophilicity and in vitrostability were explored. Studies of the biodistribution and metabolism of the radiotracer were investigated in normal rats. PET imaging of the tracer in KB tumor-bearing mice at different time points were evaluated.Results1. Labeling conditions:when the concentration of NOTA-Folate was lmg/mL, the concentration of AlC13 was lg/L, and then the reaction mixture wasincubated at 100-110℃ for 20 minutes. The novel radiotracer Al18F-NOTA-Folate was produced in good radiochemical yields (100%) and high specific activity(7.2GBq/umol), the radiochemical purity was more than 99%, thus, further purification is unnecessary.2.The lipid water partition coefficient:logP was equal to log counts in ncaprylic alcohol divide counts in water, the calculated logP was equal to -2.32±0.10 (n=3), indicates good hydrophilicity.3. In vitro stability:the tracer was incubated at room temperature in PBS or FBS for 120 minutes, and the labeling rate was more than 99% or 98%. Therefore, the compound has great stability.4. The distribution results of the tracer in normal rats showed that the Al18F-NOTA-Folate can be cleared quickly from blood circulation, and mainly excreted through the urinary system. Higher radioactivity was detected in the kidneys, while uptakes in other tissues such as liver, heart, spleen, lung, brain, skin and muscles were relatively low.5. Biodistribution results in KB tumor-bearing mice showed that tumor uptake was relatively high (below the kidneys and spine), while hepato-biliary system and gastrointestinal uptake were low.6. Micro-PET/CT scanning of KB tumor-bearing mice showed high and specific uptake of the radiotracer in FR-positive tumors. The ratio of tumor tissue to blood (T/NT) was about 1.58±0.65 (60min p. i.)ConelusionThe radiochemical yield of Al18F-NOTA-folate is higher than common methods (e.g. [18F]SFB).The "one pot" synthesis method has some advantages such as less time and higher yield, but still has some withdraws, low tumor to non-tumor tissue (T/NT), high uptake in skeletal system, especially in spine. The molecular imaging probe targeted FR positive tumor is promising for application in PET imaging in the future.