Direct ¹⁸F‐substitution of hydroxy groups in peptides using nonafluorobutane‐I‐sulfonyl[¹⁸F]fluoride

Abstract

Aliphatic compounds are commonly labelled with fluorine-1 8 via phase-transfer mediated nucleophilic 18F-fluorination. However, this method is only convenient for those precursors which have suitable leaving groups and are rather stable under the necessary labelling conditions. In the case of complex compounds like peptides and other biomolecules, which are often not suited for direct nucleophilic fluorination are difficult to synthesize with an appropriate leaving group, a more convenient labelling method is desirable. Nonafluorobutane-1 -sulfonylfluoride is a useful agent to directly convert an aliphatic alcohol into the fluoro-derivative (1). The reaction of the sulfonic acid fluoride with hydroxy groups in presence of a base like 1,8-di~bicyclo-[5.4.0]undec-7-en (DSU) leads to the formation of nonafluorobutane sulfonic esters. The fluoride ion which is released in the course of esterification reacts in a consecutive nucleophilic substitution with formation of the corresponding fluoro compound (cf. Scheme). Scheme: Conversion of aliphatic alcohols into alkylfluorides by nonanylfluorideThe starting n.c.a. nonafluorobutane-l-sulfonyl[18F]fluoride is generated via nucleophilic F-fluorination of an appropriate sulfonimide allowing to synthesize the pure reagent in radiochemical yields of 85 5 % within 15 min. Due to the relatively low boiling point of the ["F]nonanylfluoride it is possible to distil off the pure synthon in the course of its foimation. According to a consecutive reaction sequence the "F-fluorination of an alcohol would only work for statistical reasons if the amount of the hydroxy compound is in the same range as the ~ulfonyl[~~F]fluoride and it requires that the reaction takes place in a very small volume. In order to prove the dependence of the radiochemical yield on the amount of nonafluorobutane-1-sulfonylfluoride 18

Utility of 1,3,4,6‐tetra‐O‐acetyl‐2‐deoxy‐2‐[18F]fluoro‐glucopyranoside for no‐carrier‐added 18F‐glycosylation of amino acids

“…1 H-and19 F-NMR were consistent with the literature data 39,40. N a -(Phenylmethoxycarbonyl)-O-(3,4,6-tri-O-acetyl-2-deoxy-2-fluoro-d-glucopyranosyl)-l-serine phenylmethyl ester(9)…”

“…Thus, additional and improved radiofluorination techniques are urgently required in the field of molecular imaging. Such developments include the approach toward direct 18 F-substitution of hydroxy groups in peptides, 9 the development of a chemo-enzymatic 18 F-glycosylation method 10 and, more recently, the use of [ 18 F]fluorothiols for chemoselective labelling of peptides. 11 Furthermore, Poethko et al developed a convenient and high yielding 18 Flabelling method for peptides by oxime conjugation of [ 18 F]fluorobenzaldehyde with unprotected aminooxy peptides providing an important improvement in the search for improved 18 F-labelling methodologies.…”

PyFluor: A Low-Cost, Stable, and Selective Deoxyfluorination Reagent

“…A 18 F-variant of a deoxyfluorination remains an attractive but elusive alternative approach to aliphatic C– 18 F bond formation. Thus far, all reported deoxy-radiofluorinations require a 19 F carrier in the form of an unlabeled reagent in order to generate enough activated electrophile to react with the nanomolar quantities of 18 F available under labeling conditions . Furthermore, deoxyfluorination reagents featuring multiple reactive fluorine equivalents (such as DAST) cannot be made isotopically pure, again due to low 18 F concentration.…”

18F-Fluorothiols: A New Approach To Label Peptides Chemoselectively as Potential Tracers for Positron Emission Tomography

“…The positron emitter fluorine-18 (T 1/2 ) 110 min) as a widespread positron emitter has been widely used to radiolabel peptides and proteins of medical interest. Although there are reports on direct incorporation of 18 F into peptides (6,7), the most promising approach still relies on the use of prelabeled 18 F reagents. The majority of known 18 F reagents for peptide and protein labeling are targeting primary amino groups such as the N-terminus or lysine side chains.…”

“…The positron emitter fluorine-18 ( T 1/2 = 110 min) as a widespread positron emitter has been widely used to radiolabel peptides and proteins of medical interest. Although there are reports on direct incorporation of 18 F into peptides ( , ), the most promising approach still relies on the use of prelabeled 18 F reagents.…”