Oxalic Acid Supported Si–¹⁸F-Radiofluorination: One-Step Radiosynthesis of N-Succinimidyl 3-(Di-tert-butyl[¹⁸F]fluorosilyl)benzoate ([¹⁸F]SiFB) for Protein Labeling

Abstract

N-Succinimidyl 3-(di-tert-butyl[(18)F]fluorosilyl)benzoate ([(18)F]SiFB), a novel synthon for one-step labeling of proteins, was synthesized via a simple (18)F-(19)F isotopic exchange. A new labeling technique that circumvents the cleavage of the highly reactive active ester moiety under regular basic (18)F-labeling conditions was established. In order to synthesize high radioactivity amounts of [(18)F]SiFB, it was crucial to partially neutralize the potassium oxalate/hydroxide that was used to elute (18)F(-) from the QMA cartridge with oxalic acid to prevent decomposition of the active ester moiety. Purification of [(18)F]SiFB was performed by simple solid-phase extraction, which avoided time-consuming HPLC and yielded high specific activities of at least 525 Ci/mmol and radiochemical yields of 40-56%. In addition to conventional azeotropic drying of (18)F(-) in the presence of [K(+)⊂2.2.2.]C(2)O(4), a strong anion-exchange (SAX) cartridge was used to prepare anhydrous (18)F(-) for nucleophilic radio-fluorination omitting the vacuum assisted drying of (18)F(-). Using a lyophilized mixture of [K(+)⊂2.2.2.]OH resolubilized in acetonitrile, the (18)F(-) was eluted from the SAX cartridge and used directly for the [(18)F]SiFB synthesis. [(18)F]SiFB was applied to the labeling of various proteins in likeness to the most commonly used labeling synthon in protein labeling, N-succinimidyl-4-[(18)F]fluorobenzoate ([(18)F]SFB). Rat serum albumin (RSA), apo-transferrin, a β-cell-specific single chain antibody, and erythropoietin were successfully labeled with [(18)F]SiFB in good radiochemical yields between 19% and 36%. [(18)F]SiFB- and [(18)F]SFB-derivatized RSA were directly compared as blood pool imaging agents in healthy rats using small animal positron emission tomography. Both compounds demonstrated identical biodistributions in healthy rats, accurately visualizing the blood pool with PET.

18F-Labeled Silicon-Based Fluoride Acceptors: Potential Opportunities for Novel Positron Emitting Radiopharmaceuticals

“…The recent implementation of the “Munich method” alongside the SiFA-IE labeling approach for peptide and protein labeling [43, 46, 58, 59] offers unique and unequalled simplicity, where, starting from commercially available [ 18 F]F − /[ 18 O]H 2 O, it is possible to deliver [ 18 F]SiFA radiopharmaceuticals using only room temperature transformations and facile cartridge-based manipulations. Following this approach, the 18 F-labeling of complex unprotected biomolecules becomes almost as easy as using a 99m Tc-kit.…”

Synthesis of new 18F-radiolabeled silicon-based nitroimidazole compounds

“…9 Precursor 17a and 17b were prepared as reported by Kostikov (Scheme 3). 25,26 Compounds 12a and 12b were synthesized by nucleophilic substitution of di-tert-butyldifluorosilane and ditert-butylchlorosilane respectively, starting from the reaction between ((3-bromobenzyl)oxy)(tert-butyl)dimethylsilane and tertBuLi. Acidic deprotection afforded compounds 13a and 13b in good yields.…”

Synthesis of fluorine-18 radio-labeled serum albumins for PET blood pool imaging

“…The copper(I)-catalyzed cycloaddition of azides with terminal alkynes to form 1,2,3-triazole has proved to be particularly valuable for efficient 18 F labeling of biomolecules. Ramenda et al has reported 18 F-labelled sulfonamide-based click chemistry building blocks to radiolabel HAS [21], A non-conventional Si- 18 F bonded prosthetic group has also been used to radiolabel serum albumin [22], [23]. In this approach a prosthetic group for non-site-specific protein labeling was designed and synthesized in one step by simple 19 F– 18 F isotopic exchange.…”