2.3 Labeling methods

2 Research Method Development

2.3 Labeling methods

Pendant N-2-fluoroethyl groups have featured prominently as sites for labeling tracers with fluorine-18. A new efficient substitutionreduction pathway was developed for producing N-[¹⁸F](2-fluoro)ethylanilines (ArNRCOCH₂Br + ¹⁸F- —> ArNRCOCH₂¹⁸F —> ArNRCH₂CH₂¹⁸F; R = H, Me).⁷ An unexpected benefit in decay-corrected radiochemical yield (RCY) from inclusion of trace water (~ 0.1 %) in the initial reaction of [¹⁸F]fluoride ion was demonstrated. The efficiency of this step was exploited in the high yield synthesis of a new radiotracer, [¹⁸F]PBR06 (12), for ‘peripheral benzodiazepine receptors’ (PBR).⁸

Aryl [¹⁸F]fluoromethoxy groups (ArOCH₂¹⁸F) feature in several useful PET radiotracers (e.g. [¹⁸F]SPA-RQ; 7), and are generally introduced by two-step radiochemistry where the second step is the reaction of a phenol precursor with [¹⁸F]fluoromethyl bromide (ArOH + BrCH₂¹⁸F —> ArOCH₂¹⁸F). We showed that inclusion of trace water in the preparation of the labeling agent (CH₂Br₂ + ¹⁸F- —> BrCH₂¹⁸F) appreciably improves RCY.⁹ A new method was developed for the single-step preparation of [¹⁸F]fluoromethoxyarenes in up to 67% RCY from easily prepared 1-((methylsulfinyl)-methoxy)arenes and [¹⁸F]fluoride ion (ArOCH₂S(O)Me + ¹⁸F- —> ArOCH₂¹⁸F).¹⁰ [¹⁸F]Fluoromethylthio-arene analogs (ArSCH₂¹⁸F) of [¹⁸F]fluoromethoxy-type radiotracers are often of potential interest. A single-step procedure was devised for preparing such compounds in up to 75% RCY from S-chloromethylarenes and [¹⁸F]fluoride ion (ArSCH₂Cl + ¹⁸F- —> ArSCH₂¹⁸F).¹¹

It has generally been considered that aromatic nucleophilic substitution with [¹⁸F]fluoride ion (XArY + ¹⁸F- —> XAr¹⁸F) may only take place in substrates bearing an activating (electron-withdrawing) group (X) in ortho or para orientation to a good leaving group (Y). We are interested to open up methods for introducing [¹⁸F]fluoride ion into meta positions. Following preliminary investigations,¹² the radiosyntheses of meta-[¹⁸F]fluoro benzenes from meta-nitro benzenes was investigated thoroughly and conditions for obtaining acceptable RCYs established.¹³ These results expand the applicability of [¹⁸F]fluoride ion as a readily available cyclotron-produced labeling agent. We exploited these findings to improve the preparation of a ‘literature’ mGluR5 radiotracer, [¹⁸F]FMTEB (13).¹⁴ We further showed that aromatic nucleophilic substitution with [¹⁸F]fluoride ion may take place in 2-substituted thiazoles.¹⁵ 2-Substituted thiazolyl groups are present in some receptor ligands, notably for mGluR5 (e.g. 13).

In 1995, Dr. Pike introduced reactions of diaryliodonium salts with [¹⁸F]fluoride ion as a route for the single-step incorporation of high specific radioactivity fluorine-18 into electron-rich arenes (Ar₂I+X- + ¹⁸F^- —> ArI + Ar¹⁸F).¹⁶ This had previously been very difficult to achieve by other means (e.g. Wallach or Balz-Schiemann reactions), especially in elaborate structures, including important PET radiopharmaceuticals. Since that time Dr. Pike has maintained collaboration with Drs. D.A. Widdowson (Imperial College; U.K.) and M.A. Carroll (formerly Imperial College, now Newcastle U., U.K.) in this area. New methods for the preparation of the required iodonium salts were developed^17,18 and the ring selectivity and scope of the process investigated.¹⁹ The process was also modeled theoretically.^20,21 Part of this work was recently patented.²² Other groups^23,24,25,26 are avidly investigating and exploiting this approach, including GE Healthcare, who have recently issued two patents on this topic.^27,28 We now plan a series of papers on our findings in this area in relation to iodonium salt structure,²⁹ synthesis,^30,31 reactivity³² and their conversion into electron-rich fluoroarenes, such as L-2-fluoro-tyramine (14),³³ L-6-fluoro-m-tyrosine (15)³⁴ and L-6-fluoro-dopamine (16) ^{35, 36}.

A new method was devised for the efficient single-step radiosynthesis of an aryl [¹¹C]methyl thioether from an S-protected precursor (ArSCH₂CH₂CO₂Me + ¹¹CH₃I —> ArS¹¹CH₃), and applied to the preparation of an experimental radioligand, [S-methyl- ¹¹C]thionisoxetine (18).⁴⁰