A micro-reactor was applied to produce ortho-substituted [ 18 F]fluoroarenes from the reactions of cyclotron-produced [ 18 F]fluoride ion (t 1/2 = 109.7 min) with diaryliodonium salts. The micro-reactor provided a very convenient means for running sequential reactions rapidly with small amounts of reagents under well-controlled conditions, thereby allowing reaction kinetics to be followed and Arrhenius activation energies (E a ) to be measured. Prepared symmetrical iodonium chlorides (Ar 2 I + Cl − ) rapidly (< 8 min) gave moderate (Ar = 2-MeOC 6 H 4 , 51%) to high (Ar = Ph or 2-MeC 6 H 4 , 85%) decay-corrected radiochemical yields (RCYs) of a single radioactive product (Ar 18 F). Reaction velocity with respect to Ar group was 2-MeOC 6 H 4 < Ph < 2-MeC 6 H 4 . Activation energies were in the range 18-28 kcal/mol. Prepared unsymmetrical salts (e.g., 2-RC 6 H 4 I + 2'-R'C 6 H 4 X − ; X = Cl or OTs) also rapidly gave two products (2-RC 6 H 4 18 F and 2-R'C 6 H 4 18 F) in generally high total RCYs (79-93%). Selectivity for product [ 18 F]fluoroarene was controlled by the nature of the ortho substituents. The power of ortho substituents to impart an ortho effect was in the following order, 2,6-di-Me > 2,4,6-tri-Me > Br > Me > Et ∼ i Pr >> H > OMe. For (2-methyphenyl) (phenyl)iodonium chloride, the time-course of reaction product selectivity was constant and consistent with the operation of the Curtin-Hammett Principle. These results will aid in the design of diaryliodonium salt precursors to 18 F-labeled tracers for molecular imaging.

Effective methods for the introduction of the short-lived positron-emitter fluorine-18 (t1/2 = 109.7 min) at high specific radioactivity into fluoroarenes are valuable for the development of radiotracers for molecular imaging with positron emission tomography. Here we have explored the scope of the radiofluorination of diaryliodonium salts with no-carrier-added [18F]fluoride ion for the preparation of otherwise difficult to access meta-substituted [18F]fluoroarenes. A microfluidic reaction platform was used to establish optimal radiochemical yields. Rapid, high yielding and selective radiofluorinations were achieved in unsymmetrical diaryliodonium tosylates (ArI+Ar’TsO−) in which Ar carried either a meta electron-withdrawing (CN, NO2, CF3) or a meta electron-donating (Me or MeO) group, and in which the partner aryl group (Ar’) was relatively electron-rich, such as Ph, 3-Me-C6H4, 4-MeO-C6H4, 2-thienyl or 5-Me-2-thienyl. The radiofluorination of appropriate diaryliodonium tosylates is therefore a generally useful method for the preparation of simple [18F]m-fluoroarenes ([18F]ArF).

3-Fluoro-1-((thiazol-4-yl)ethynyl)benzenes constitute an important class of high-affinity metabotropic glutamate subtype 5 receptor (mGluR5) ligands, some of which have been labeled with fluorine-18 (t1/2 = 109.7 min), to provide radioligands for molecular imaging of brain mGluR5 in living animal and human subjects with positron emission tomography (PET). Labeling in the 3-fluoro position of such ligands can be achieved through aromatic nucleophilic substitution of a halide leaving group with [18F]fluoride ion when a weakly activating m-nitrile group is present, but is generally very low yielding (< 8%). Here we used a microfluidic reaction platform to show that greatly enhanced (up to 6-fold) radiochemical yields can be achieved from suitably synthesized diaryliodonium tosylate precursors. The presence of a m-nitrile or other activating group is not required. Similar conditions were adopted in a more conventional automated radiochemistry platform having a single-pot reactor, to produce mGluR5 radioligands in useful radioactivities for PET imaging.