Syntheses of 11C- and 18F-labeled carboxylic esters within a hydrodynamically-driven micro-reactor

Abstract

Carboxylic esters were successfully labeled with one of two short-lived positron-emitters, carbon-11 or fluorine-18, within a hydrodynamically-driven micro-reactor. The non-radioactive methyl ester was obtained at room temperature; its yield increased with higher substrate concentration and with reduced infusion rate. Radioactive methyl ester was obtained from the reaction of (10 mM) with in 56% decay-corrected radiochemical yield (RCY) at an infusion rate of 10 microL min(-1), and when the infusion rate was reduced to 1 microL min(-1), the RCY increased to 88%. The synthesis of the non-radioactive fluoroethyl ester from and required heating of the micro-reactor on a heating block at 80 degrees C (14-17% RCY), whilst the corresponding radioactive from and was obtained in 10% RCY. The radioactive 'peripheral' benzodiazepine receptor ligand was obtained from the reaction of acid with labeling agent in 45% RCY at an infusion rate of 10 microL min(-1). When the infusion rate was reduced to 1 microL min(-1), the RCY increased to 65%. The results exemplify a new methodology for producing radiotracers for imaging with positron emission tomography that has many potential advantages, including a requirement for small quantities of substrates, enhanced reaction, rapid reaction optimisation and easy product purification.

Fig. 1

Effect of infusion rate and reagent concentration on the yield of ester 4a from the reactions of acid 1 (10 mM) with 2a (10 mM) (●); 1 (5 mM) with 2a (5 mM) (■); 1 (2 mM) with 2a (2 mM) (▲) and RCYs of ¹¹C-labeled ester 4b from the reaction of acid 1 (10 mM) with 2b (○), 1 (5 mM) with 2b (□) and 1 (2 mM) with 2b (△). All reactions were performed at room temperature.

Fig. 2

Effect of infusion rate and reagent concentration on the yield of ester 5a from the reaction of acid 1 (10 mM) with 3a (10 mM) (●) and 1 (5 mM) with 3a (5 mM) (■) at 80 °C in DMF, and the RCY of ester 5b from the reaction of acid 1 (5 mM) with 3b at 80 °C (□).

Fig. 3

The effect of infusion rate on the yield of ester 7a from the reaction of acid 6 (5 mM) with 2a (5 mM) (●) and the RCYs of ester 7b from the reaction of acid 6 (5 mM) with 2b (○). All reactions were performed at room temperature.

Scheme 1

Labeling of carboxylic esters with ¹¹C or ¹⁸F.

Scheme 2

Schematic representation of the reagent placement and flow direction within the micro reactor.

Scheme 3

Synthesis of non-radioactive or ¹¹C-labeled peripheral benzodiazepine receptor ligand.