2-[18F]Fluorophenylalanine: Synthesis by Nucleophilic 18F-Fluorination and Preliminary Biological Evaluation

Abstract

2-[18F]Fluorophenylalanine (2-[18F]FPhe), a promising PET tracer for imaging of cerebral infarction and tumors, was efficiently prepared from an easily accessible iodonium salt precursor using Cu-mediated radiofluorination under ‘low base’ or ‘minimalist’ conditions. Whereas significant racemization was initially observed if the ‘minimalist’ protocol was applied for radiolabeling, it was completely suppressed by the careful adjustment of 18F– preprocessing. The initial biological study revealed a higher uptake of 2-[18F]FPhe in different tumor cells in comparison to that of [18F]FET. In contrast to 4-[18F]FPhe, which suffered from rapid defluorination in vivo, 2-[18F]FPhe demonstrated a sufficient in vivo stability. Conclusively, 2-[18F]FPhe is a promising PET probe that is now readily available using Cu-mediated radiofluorination under ‘minimalist’ or ‘low base’ conditions. The simplicity of the translation of the proposed procedures to automated synthesis modules allows a broad biological evaluation of 2-[18F]FPhe. Notably, a novel protocol for the preparation of N-Boc protected amino acids from the respective Ni-Schiff base complexes was developed that avoided application of strongly acidic conditions.

Alcohol-Supported Cu-Mediated 18F-Fluorination of Iodonium Salts under “Minimalist” Conditions

“…( S )-Ni-BPB-Gly [27] was alkylated with 3-iodobenzyl bromide, affording the Ni(II) complex 14 as a single ( S , S )-isomer. 14 was decomposed by transchelation with the ditetraethylammonium salt of DTPA [28] furnishing 3-IPhe, which was N -Boc and O - t Bu protected in two sequential steps to give Boc-3-IPhe-O t Bu 15 in 56% over four steps with a single chromatographic purification. The latter was transformed into Boc-3-(SnMe 3 )Phe-O t Bu which in turn was allowed to react with MesI(OH)OTs affording the iodonium salt 12 in 20% yield over six steps.…”

“…N -mono-Boc protected 12 and 13 as well as N , N -di-Boc protected precursors of 2-[ 18 F]FPhe and 4-[ 18 F]FPhe, 11 and 14 [28], were successfully radiolabeled affording protected radiolabeled FPhes, in RCCs of 85-86%, 62%, 59–68%, and 80%, respectively (Table 1; Scheme 3). Finally, deprotection with 12 n HCl and HPLC purification furnished 2–4-[ 18 F]FPhe in isolated RCYs of 22–30%, 37–43%, and 67–69%, respectively, within 110 min.…”

“…Importantly, the novel procedure enabled the production of 3- and 4-[ 18 F]FPhes in a remote-controlled synthesis unit. Remarkably, whereas, the application of the conventional “minimalist” protocol led to significant loss of enantiopurity [formation of up to 20% of the ( R )-isomer] in the case of 2-[ 18 F]FPhe [28], the novel procedure delivered this radiotracer with >95% enantiomeric excess ( ee ). The observed suppression of racemization in the case 2-[ 18 F]FPhe could be explained as follows.…”

“…The thermally unstable iodonium bicarbonate and carbonate iodonium salts could form as a result of a partial anion exchange with the anion exchange resin in HCO 3 – and/or CO 3 2– form during the elution of [ 18 F]fluoride. In the subsequent MeOH evaporation step CO 2 and H 2 O will be lost affording, in the case of the ortho -iodonium salt 9 , the corresponding betaine with concurrent loss of stereointegrity (refer to [28] for a more detailed discussion). Consequently, avoiding MeOH evaporation suppresses racemization.…”

“…(4-Methoxyphenyl)(mesityl)iodonium tosylate ( 1 ·OTs) [29], (4-methoxyphenyl)(mesityl)iodonium tetrafluoroborate ( 1 ·BF 4 ) [17,29], (phenyl)(mesityl)iodonium tetrafluoroborate [30], (3-carbonylphenyl)(mesityl)iodonium tetrafluoroborate [30], 2-{2-[(2 S )-2-{bis[( tert -butoxy)carbonyl]amino}-3-( tert -butoxy)-3-oxopropyl]phenyl}(2,4,6-trimethylphenyl)iodanium tetrafluoroborate ( 11 ) [28], 4-{2-[(2 S )-2-{[( tert -butoxy)carbonyl]amino}-3-( tert -butoxy)-3-oxopropyl]phenyl}(2,4,6-trimethylphenyl)iodanium tetrafluoroborate ( 13 ) [17], 4-{2-[(2 S )-2-{bis[( tert -butoxy)carbonyl]amino}-3-( tert -butoxy)-3-oxopropyl]phenyl}(2,4,6-trimethylphenyl)iodanium tetrafluoroborate [28], ( S )-Ni-BPB-Gly [27] hydroxy{[(4-methylphenyl)sulfonyl]oxy}(2,4,6-trimethylphenyl)-λ3–iodine [31] were prepared according to the literature or modified literature procedures.…”