Designing kinetically stable aryltrifluoroborates as ¹⁸F‐capture agents for PET imaging

Abstract

One‐step 18F‐radiolabeling of peptides and other large biomolecules has been challenged by a critical gap in chemical compatibility between fluoride anion, which is unreactive as a nucleophile in water, and large biomolecules such as peptides that are insoluble in dry solvents. Traditionally, this disparity has been overcome through the preliminary synthesis of an 18F‐labeled radioprosthetic group that is appended to peptides following at least one additional step. Ideally, however, peptides should be labeled in a single aqueous step. Hence, we proposed the use of arylboronic acids as captors of aqueous 18F‐fluoride ion to simplify the radiosynthesis of 18F‐aryltrifluoroborate bioconjugates. Yet, the use of aryltrifluoroborates as radioprosthetic groups can only be considered if kinetically stable ones can be designed. Herein, we discuss the kinetic and thermodynamic parameters review our previous use of a Hammett analysis that can inform the design of kinetically stable 18F‐labeled aryltrifluoroborates for use as novel radioprosthetic groups. Copyright © 2014 John Wiley & Sons, Ltd.

[18F]-Organotrifluoroborates as Radioprosthetic Groups for PET Imaging: From Design Principles to Preclinical Applications

“…32 In addition, ortho substituents sterically clash with the fluorine atoms of difluoroborane 5, disfavoring its production and thereby retarding solvolysis of the trifluoroborate. 29 Finally, we found that electron-deficient N-heterocycles significantly retard solvolysis. 33,34 With this understanding, we designed a new EWGsubstituted ArBF 3 − (Figure 6), in which the three fluorine atoms on the ring predictably increased the solvolytic half-life to ∼1000 min while the m-carboxylate enabled bioconjugation via an amide bond, which further enhanced the stability (σ m = 0.28 for −CONH 2 vs −0.1 for −COO − ).…”

“…We therefore performed a Hammett analysis to quantify the effects of EDGs and EWGs in terms of published σ and σ + values; log­( k solv ) is negatively correlated with the sum of the σ values: ρ ≈ −1 ( R ≈ 0.9) . In addition, ortho substituents sterically clash with the fluorine atoms of difluoroborane 5 , disfavoring its production and thereby retarding solvolysis of the trifluoroborate . Finally, we found that electron-deficient N-heterocycles significantly retard solvolysis. , …”

“…Although the free energy (ΔG°′) is estimated to be uphill by 3 kcal/mol, 29 because K eq is third-order in fluoride, solvolysis is highly favored (even at 25 mM ArBF 3 − or 100 mM F). 27,30 At high dilution (in vivo), the equilibrium ArBF 3 − concentration approaches zero.…”

“…Moreover, at pH > 4, liberated HF is deprotonated, causing the reaction to be even more irreversible. This is appreciated by considering K eq for ArBF 3 – solvolysis (eq ): Although the free energy (Δ G °′) is estimated to be uphill by 3 kcal/mol, because K eq is third-order in fluoride, solvolysis is highly favored (even at 25 mM ArBF 3 – or 100 mM F). , At high dilution (in vivo), the equilibrium ArBF 3 – concentration approaches zero. Hence, ArBF 3 – solvolysis is solely under kinetic control (as is the case for all chemical bonds in all radiotracers).…”

2,6-Bis(trifluoromethyl)phenylboronic Esters as Protective Groups for Diols: A Protection/Deprotection Protocol for Use under Mild Conditions

“…It is well-known that boronic acids form covalent bonds with 1,2- or 1,3-diols to generate five- or six-membered cyclic boronic esters under mild and neutral conditions. , Therefore, boronic acids such as phenyl boronic acid and polymer-supported boronic acids have been used as protective or transient masking agents for diols. ,, However, cyclic arylboronic esters, except those derived from highly hindered substrates, − are susceptible to hydrolysis, even under neutral conditions. Consequently, this poor stability limits the reaction conditions under which this protective strategy may be applied.…”