Optimization of precursor synthesis, formulation and stability of 1'-[18F]fluoroethyl-β-D-lactose ([18F]FEL) for preclinical studies in detection of pancreatic cancer.

Introduction1'-[(18)F]Fluoroethyl-β-D-lactose ([(18)F]FEL) is a new PET imaging agent for early detection of pancreatic cancer and hepatocellular carcinoma. We previously reported the syntheses of [(18)F]FEL using a bromo- and a tosyl- precursor, followed by an improved method using a nosyl-precursor. However, some steps in the synthesis of the precursor appeared to be problematic producing low yields. Here, we report on an optimized method for synthesis of the precursor and production of [(18)F]FEL; we also describe [(18)F]FEL's formulation and stability.MethodsAcetylation of D-lactose 1 was performed following a literature procedure to obtain 1',2',3',6',2,3,4,6-D-lactose octa-acetate 2a/2b. Bromination of 2a/2b was performed using HBr/acetic acid to produce 1'-bromo-2',3',6',2,3,4,6-hepta-O-acetyl-α-D-lactose 3. Coupling of 3 with ethylene glycol was performed in the presence of Ag-tosylate and an excess of ethylene glycol to produce 4a. Compound 4a was reacted with p-nitrophenylsulfonyl chloride to produce the nosyl derivative 5. Radiofluorination of 5 was performed using K[(18)F]fluoride/kryptofix to obtain 6, which was purified by HPLC and hydrolyzed with Na-methoxide to produce 7.ResultsCompound 2 (2a/2b) was obtained in 83% yield as a mixture of two anomeric products. Compound 3 was obtained from the 2a/2b mixture in 80% yield as one product. Coupling of 3 with ethylene glycol produced 4a in 90% yield. Compound 5 was obtained in 64% yield, and radiofluorination of 5 produced 6 in 62.5% ± 7.5% yields (n=8). Hydrolysis of 6 with Na-methoxide produced 7 in 42.0% ± 7.0% yield (n=8) from the end of bombardment.ConclusionsA simple 4-step synthesis of the precursor, compound 5, has been achieved with improved yields. A new formulation of [(18)F]FEL has been developed that allows the product to remain stable at ambient temperature for use in animal studies. This improved synthesis of the precursor and stable formulation of [(18)F]FEL should be useful for routine production of the radiotracer and its preclinical and, possibly, clinical applications.