Mechanistic approach of the difference in non-enzymatic hydrolysis rate between the L and D enantiomers of no-carrier added 2-[18F]fluoromethyl-phenylalanine

✍ Scribed by Ken Kersemans; John Mertens; Frank De Proft; Paul Geerlings

• Publisher: John Wiley and Sons
• Year: 2010
• Tongue: French
• Weight: 227 KB
• Volume: 54
• Category: Article
• ISSN: 0022-2135
• DOI: 10.1002/jlcr.1811

✦ Synopsis

Abstract

No‐carrier added (n.c.a.) 2‐[^18^F]fluoromethyl‐l‐phenylalanine was found to be very sensitive to hydrolysis in aqueous solutions. This problem was solved partially by the addition of calcium ions (0.04 M), increasing the shelf‐life to at least 6 h. In this paper the defluorination reaction was studied in detail to elucidate its mechanism. Therefore, L and D enantiomers of 2**‐[^18^F]FMP and 4‐[^18^F]FMP were synthesized, as well as 2‐[^18^F]fluoromethyl‐phenethylamine and 4‐[^18^F]fluoromethyl‐phenethylamine, both decarboxylated ‘mimetic’ molecules of the amino acid analogues. Radiosynthesis, using a customized Scintomics automatic synthesis hot__box__^three^ module, resulted in a high overall yield and a radiochemical purity of >99%. The defluorination rates of all compounds were studied by HPLC. The L enantiomer of n.c.a 2‐[^18^F]FMP defluorinated seven times faster than the D enantiomer and 2‐[^18^F]fluoromethyl‐phenethylamine. Both enantiomers of 4‐**[^18^F]FMP and 4‐[^18^F]fluoromethyl‐phenethylamine were stable. From these data, the reaction mechanism, involving two distinct intramolecular interactions, was derived. First, the interaction between the amine and the benzylic fluorine weakens the carbon–fluorine bond. Secondly, the formation of a second hydrogen bridge between the carboxyl group and one of the benzylic hydrogen atoms renders the fluorine atom even more susceptible to hydrolysis. The latter interaction induces an additional chiral center. The probability of its formation differs considerably between L and D enantiomers of n.c.a. 2‐[^18^F]FMP, which explains the difference in hydrolysis rate. Copyright © 2010 John Wiley & Sons, Ltd.