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

Introduction: 1'-[¹⁸F]Fluoroethyl-β-d-lactose ([¹⁸F]FEL) is a new PET imaging agent for early detection of pancreatic cancer and hepatocellular carcinoma. We previously reported the syntheses of [¹⁸F]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 [¹⁸F]FEL; we also describe [¹⁸F]FEL's formulation and stability. Methods: Acetylation 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[¹⁸F]fluoride/kryptofix to obtain 6, which was purified by HPLC and hydrolyzed with Na-methoxide to produce 7. Results: Compound 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. Conclusions: A simple 4-step synthesis of the precursor, compound 5, has been achieved with improved yields. A new formulation of [¹⁸F]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 [¹⁸F]FEL should be useful for routine production of the radiotracer and its preclinical and, possibly, clinical applications.