Skip to content

Molecular Imaging Branch

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- —> ArNRCOCH2 18F —> ArNRCH2CH2 18F; 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 (ArOCH2 18F) 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 + BrCH2 18F —> ArOCH2 18F). 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- —> ArOCH2 18F).10 [18F]Fluoromethylthio-arene analogs (ArSCH2 18F) 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- —> ArSCH2 18F).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 developed17,18 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 groups23,24,25,26 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