Biologically stable [F-18]-labeled benzylfluoride derivatives

Use of the [F-18]-fluoromethyl phenyl group is an attractive alternative to direct fluorination of phenyl groups because the fluorination of the methy l group takes place under milder reaction conditions. However, we have foun d that 4-FMeBWAY showed femur uptake equal to that of fluoride up to 30 min in rat whereas 4-FMeQNB had a significantly lower percent injected dose pe r gram in femur up to 120 min; For these and other benzylfluoride derivativ es, there was no clear in vivo structure-defluorination relationship. Becau se benzylchlorides (BzCls) are known alkylating agents, benzylfluorides may be alkylating agents as well, which may be the mechanism of defluorination , On this basis, the effects of substitution on chemical stability were eva luated by the 4-(4-nitro-benzyl)-pyridine (NBP) test, which is used to esti mate alkylating activity with NBP. The effect of substitution on the alkyla ting activity was evaluated for nine BzCl derivatives: BzCl; 3- or 4-methox y (electron donation) substituted BzCl; 2-, 3-, or 4-nitro (electron withdr awing) substituted BzCl; and 2-, 3-, or 4-chloro (electron withdrawing) sub stituted BzCl. Taken together, the alkylating reactivity of 3-chloro-BzCl w as the weakest, This result was then applied to [F-18]-benlylfluoride deriv atives and in vivo and in vitro stability were evaluated. Consequently, 3-c hloro-[F-18]-benzylfluoride showed a 70-80% decrease of defluorination in b oth experiments in comparison with [F-18]-benzylfluoride, as expected. More over, a good linear relationship between in vivo femur uptake and in vitro hepatocyte metabolism was observed with seven F-18-labeled radiopharmaceuti cals, which were benzylfluorides, alkylfluorides, and arylfluorides. Appare ntly, the [F-18]-fluoride ion is released by metabolism in the liver in viv o. In conclusion, 3-chloro substituted BzCls are the most stable, which sug gests that 3-chloro benzylfluorides will be the most chemically stable comp ound. This result should be important in future design of radioligands labe led with a benzylfluoride moiety. NUCL MED BIOL 27;2:163-168, 2000. (C) 200 0 Elsevier Science Inc. All rights reserved.