Fluoride-18 radiolabeling of peptides bearing an aminooxy functional group to a prosthetic ligand via an oxime bond

Abstract

We have developed a novel F-18 prosthetic ligand named fluoro-PEG-benzaldehyde (FPBA) 1. [18F]-FPBA 1 is formed in situ from its radiolabeled precursor [18F]6. Compound 6 is efficiently synthesized in four steps starting from commercially available 6-bromo-3-pyridine carbaldehyde 2. [18F]-FPBA was evaluated as a prosthetic ligand to radiolabel three cyclic peptides bearing an aminooxy functional group at the N-terminus position. Acetal [18F]6 is purified by either solid-phase extraction (SPE) or reverse-phase HPLC with the overall radiochemical yields (RCY) and radiochemical purity (RCP) in very close agreement. The SPE purification process has the advantage of shorter reaction times (71–87 min for entire reaction sequence), while the use of the reverse-phase HPLC purification process allows the use of up to fifty times less of the expensive synthetic peptides (~ 50 nmol) in the oxime coupling reaction. We have demonstrated an efficient methodology in the production of [18F]-FPBA 1 and demonstrated its use as a prosthetic ligand for the labeling of peptides possessing an aminooxy functional group.

Solid-phase synthesis and fluorine-18 radiolabeling of cycloRGDyK

“…[12] Several approaches to the radiolabeling of cRGDyK ( 4 ) have been reported including: the use of activated ester N -succinimidyl-4-[ 18 F]-fluorobenzoate ([ 18 F]SFB, [13] activated ester p -nitrophenyl-2-fluoropropionate ([ 18 F]NFP, [11] conjugation of 2-[ 18 F]-fluorodeoxyglucose ([ 18 F]FDG), [14] and reaction of aldehydes to form oximes. [15] …”

“…[14] Similarly, a novel aldehyde, [ 18 F]-fluoro-PEG-nicotinicaldehyde prepared in four steps has been coupled to various cyclic peptide oxyamines in TFA/water solution at 70 °C for 30 min to afford the peptide oximes with radiochemical decay corrected yields ranging from 21–35%. [15] These methods, however, used between 2–5 mg of purified peptide. The most comparable radiolabeling method to the one reported here was carried out by Chen and co-workers where the ε-amine of the lysine in cRGDyK( 4 ) (0.1 mg, purified peptide) was labeled with [ 18 F]SFB in less than 2 hours with 20–25% decay corrected yield and specific activity of 230 GBq/μmol.…”

18F‐Labeling of Sensitive Biomolecules for Positron Emission Tomography

“…A variety of 18 F-containing aldehydes/hemi-acetal prosthetic groups such as 6-(2- [18 F]fluorohexyloxy)nicotinaldehyde ( 51 ), [53] 4-formylbenzene-1-sulfonyl [18 F]fluoride ( 52 ), [54] 3-formyl-2,4,6-trimethylbenzene-1-sulfonyl [18 F]fluoride ( 53 ), [54] 2-(2-(2- [18 F]fluoroethoxy)ethoxy)acetaldehyde ( 54 ), [55] 4- [18 F]fluorobenzaldehyde ( [18 F]FBA, 55 ), 55b p -(di- tert -butyl [18 F]fluorosilyl)benzaldehyde ( [18 F]SiFA-A, 56 ), [56] 2-deoxy-2- [18 F]fluoroglucose ( [18 F]FDG, 57 ) [57] and 5-deoxy-5- [18 F]fluororibose( [18 F]FDR, 58 ) [58] have been developed for 18 F-labeling of biomolecules (Figure 9). …”

“…Bioconjugation reactions featuring oximes formation have also drawn extensive attention in the field and are widely used for labeling aminooxy‐functionalized peptides with fluorine‐18. A variety of 18 F‐containing aldehydes/hemi‐acetal prosthetic groups such as 6‐(2‐[ 18 F]fluorohexyloxy)nicotinaldehyde ( 51 ), 4‐formylbenzene‐1‐sulfonyl [ 18 F]fluoride ( 52 ), 3‐formyl‐2,4,6‐trimethylbenzene‐1‐sulfonyl [ 18 F]fluoride ( 53 ), 2‐(2‐(2‐[ 18 F]fluoroethoxy)ethoxy)acetaldehyde ( 54 ), 4‐[ 18 F]fluorobenzaldehyde ([ 18 F]FBA, 55 ), p ‐(di‐ tert ‐butyl[ 18 F]fluorosilyl)benzaldehyde ([ 18 F]SiFA‐A, 56 ), 2‐deoxy‐2‐[ 18 F]fluoroglucose ([ 18 F]FDG, 57 ) and 5‐deoxy‐5‐[ 18 F]fluororibose([ 18 F]FDR, 58 ) have been developed for 18 F‐labeling of biomolecules (Figure ).…”

Oxime formation for fluorine-18 labeling of peptides and proteins for positron emission tomography (PET) imaging: A review

“…The aldehyde group in 30 was protected to avoid side reaction during the 18 F-fluorination step [61]. The aldehyde protecting group was removed in situ, generating aldehyde 32 under the acidic reaction conditions for peptide conjugation, e.g., in TFA/ethanol/H 2 O at 70 8C.…”