18F-Labeling of Radiotracers Functionalized with a Silicon Fluoride Acceptor (SiFA) for Positron Emission Tomography

Summary

The synthesis of fluorine-18 (¹⁸F) labeled radiopharmaceuticals for positron emission tomography typically requires months of experience. When incorporated into a radiotracer, the silicon-fluoride acceptor (SiFA) motif enables a simple ¹⁸F-labeling protocol that is independent of costly equipment and preparatory training, while reducing precursor quantity needed and utilizing milder reaction conditions.

Abstract

The para-substituted di-tert-butylfluorosilylbenzene structural motif known as the silicon-fluoride acceptor (SiFA) is a useful tag in the radiochemist's toolkit for incorporating radioactive [¹⁸F]fluoride into tracers for use in positron emission tomography. In comparison to conventional radiolabeling strategies, isotopic exchange of fluorine-19 from SiFA with [¹⁸F]fluoride is carried out at room temperature and requires minimal reaction participants. The formation of by-products is thus negligible, and purification is greatly simplified. However, while the precursor molecule used for labeling and the final radiolabeled product are isotopically discrete, they are chemically identical and are thus inseparable during purification procedures. The SiFA tag is also susceptible to degradation under the basic conditions arising from the processing and drying of [¹⁸F]fluoride. The '4 drop method', wherein only the first 4 drops of eluted [¹⁸F]fluoride are used from the solid-phase extraction, reduces the amount of base in the reaction, facilitates lower molar amounts of precursor, and reduces degradation.

Introduction

Fluorine-18 (109-minute half-life, 97% positron emission) is among the most important radionuclides for positron emission tomography (PET), a noninvasive imaging method that visualizes and quantifies the bio-distribution of radiolabeled tracers for various diseases¹. Peptides and proteins are especially difficult to label with [¹⁸F]fluoride because they require building blocks formed by multi-step syntheses². To reduce the complexity of ¹⁸F-radiolabeling, silicon-fluoride acceptor (SiFA) was recently introduced as reliable tools³. The SiFA group consists of a central silicon ....

Protocol

CAUTION: One must keep in mind that ¹⁸F is a radioactive isotope, and therefore it is necessary to carry out all procedures behind adequate shielding. Lead shielding is appropriate for this type of radiation. Be sure to wear radiation detection badges throughout the entirety of this procedure. Additionally, immediately dispose of gloves before touching anything after the synthesis, as they may be contaminated with radioactive activity. Utilize hand-foot monitors as well as pancake Geiger counters to check for contamination of sleeves, hands, and feet.

1. Azeotropic drying of ¹⁸F-anion

NOTE:

Results

The simplistic SiFA isotopic exchange can achieve high a degree of radiochemical incorporation of [¹⁸F]fluoride (60−90%) with a minimum amount of synthetic complexity (Figure 1). Most molecules can be radiolabeled with [¹⁸F]fluoride in one step without involving HPLC for purification (Figure 2). Radio-HPLC can be used for quality control purposes, wherein the ultraviolet (UV) absorbance peak of the final product should coincide with i.......

Discussion

SiFA labeling chemistry represents one of the first ¹⁸F-labeling methods employing an extraordinarily efficient isotopic exchange reaction that can be performed at room temperature. A typical radiochemical reaction relies on the formation of a carbon-fluorine bond via reaction of [¹⁸F]fluoride with a fluoride-reactive functionality through an elimination or substitution pathway. These reaction conditions are often harsh, performed at extreme pH or high temperature, and are laden with byproducts or r.......

Materials

Name	Company	Catalog Number	Comments
[18F]F-/H2[18O]O	(Cyclotron produced)	-	-
[2.2.2]Cryptand	Aldrich	291110	Kryptofix 2.2.2
Acetonitrile anhydrous	Aldrich	271004	-
Deionized water	Baxter	JF7623	-
Ethanol, anhydrous	Commercial Alcohols		-
Potassium carbonate	Aldrich	209619	-
QMA cartridge	Waters	186004540	QMA SepPak Light (46 mg) cartridge
Equipment
C-18 cartridge	Waters	WAT023501	C-18 SepPak Light cartridge
C18 column	Phenomenex	00G-4041-N0	HPLC Luna C18 250 x 10 mm, 5 µm
HPLC	Agilent Technologies	-	HPLC 1200 series
micro-PET Scanner	Siemens	-	micro-PET R4 Scanner
Radio-TLC plate reader	Raytest	-	Radio-TLC Mini Gita
Sterile filter 0.22µm	Millipore	SLGP033RS	-