Detailed radiosynthesis of [¹⁸F]mG4P027 as a positron emission tomography radiotracer for mGluR4

Abstract

We report here the detailed radiosynthesis of [ 18 F]mG4P027, a metabotropic glutamate receptor 4 (mGluR4) PET radiotracer, which showed superior properties to the currently reported mGluR4 radiotracers. The radiosynthesis in the automated system has been challenging, therefore we disclose here the major limiting factors for the synthesis via step-by-step examination. And we hope this thorough study will help its automation for human use in the future.

Fully automated radiosynthesis of [18F]mG4P027 for mGluR4 imaging

“…The reaction mixture was then diluted with 10 mL of water and passed through a C 18 Sep‐Pak to trap [ 18 F] 2 , which was washed with an additional 5 mL of water. After drying for 30 min, [ 18 F] 2 was washed off the cartridge with dry DMSO (ESI, Figure S4) and then used in the second step to give >99% conversion (based on [ 18 F] 2 ) at 135°C [21].…”

“…A large amount of water was introduced in the first Sep‐Pak purification step, and thus drying the Sep‐Pak column containing [ 18 F] 2 was critical for the second‐step reaction, which is very sensitive to water [21]. To understand the issues with the automation system, we compared the drying methods used in the manual operation and automation system by using two C 18 cartridges to trap [ 18 F] 2 from the first‐step reaction.…”

“…To develop an efficient automated protocol, we studied the key factors of the two‐step manual labeling process of [ 18 F] mG4P027 and analyzed the challenges involved in automating this process [21]. The results showed that (1) t ‐BuOH used in the first step causes problems during the Sep‐Pak trapping of [ 18 F] 2 ; (2) remaining starting martial 1 and product [ 18 F] 3 affected the second step of the reaction, in which bistosylate 1 was more reactive than [ 18 F] 2 and reacted with 4 to give 6 (if 1 was not removed); (3) both steps were sensitive to water and because a large amount of water was introduced for the first Sep‐Pak purification step, drying [ 18 F] 2 was a significant challenge; and (4) under neutral conditions, thiophenol precursor 4 easily transformed into its dimer 7 (Scheme 3).…”

“…As another possible approach, we increased the amount of 4 in the second reaction to enhance the reaction between [ 18 F] 2 and 4 . However, we found that the amount of compound 4 could not exceed 1.5 mg because 4 tended to form compounds 6 and 7 , leading to clotting caused by the poor solubility of compound 7 (Scheme 3) [21].…”

“…However, we found that the second reaction did not deliver the product [ 18 F] mG4P027, with the trapped intermediate [ 18 F]2 dried for 30 min by either helium blowing (ESI, Figure S5) or vacuum drying methods (ESI, Figure S6). A large amount of water was introduced in the first Sep-Pak purification step, and thus drying the Sep-Pak column containing [ 18 F]2 was critical for the secondstep reaction, which is very sensitive to water [21]. To understand the issues with the automation system, we compared the drying methods used in the manual operation and automation system by using two C 18 cartridges to trap [ 18 F]2 from the first-step reaction.…”