A Novel Prosthetic Group for Site-Selective Labeling of Peptides for Positron Emission Tomography

Abstract

Efficient methodologies for the radiolabeling of peptides with [(18)F]fluoride are a prerequisite to enabling commercialization of peptide-containing radiotracers for positron emission tomography (PET) imaging. It was the purpose of this study to investigate a novel chemoselective ligation reaction comprising conjugation of an [(18)F]-N-methylaminooxy-containing prosthetic group to a functionalized peptide. Twelve derivatives of general formula R1-CO-NH-Lys-Gly-Phe-Gly-Lys-OH were synthesized where R1 was selected from a short list of moieties anticipated to be reactive toward the N-methylaminooxy group. Conjugation reactions were initially carried out with nonradioactive precursors to assess, in a qualitative manner, their general suitability for PET chemistry with only the most promising pairings progressing to full radiochemical assessment. Best results were obtained for the ligation of O-[2-(2-[(18)F]fluoroethoxy)ethyl]-N-methyl-N-hydroxylamine 18 to the maleimidopropionyl-Lys-Gly-Phe-Gly-Lys-OH precursor 10 in acetate buffer (pH 5) after 1 h at 70 degrees C. The non-decay-corrected isolated yield was calculated to be 8.5%. The most encouraging result was observed with the combination 18 and 4-(2-nitrovinyl)benzoyl-Lys-Gly-Phe-Gly-Lys-OH, 9, where the conjugation reaction proceeded rapidly to completion at 30 degrees C after only 5 min. The corresponding non-decay-corrected radiochemical yield for the isolated (18)F-labeled product 27 was 12%. The preliminary results from this study demonstrate the considerable potential of this novel strategy for the radiolabeling of peptides.

Synthesis, quality control and dosimetry of the radiopharmaceutical 18F-sodium fluoride produced at the Center for Development of Nuclear Technology - CDTN

“…The main peak on the radiochromatogram obtained using HPLC for the Na 18 F test solution had approximately the same retention time (about 2 minutes) as the peak for 18 F described in literature data (Olberg et al, 2008). More than 99% of the radioactivity was related to 18 F peak (Figure 3).…”

Radiosynthesis and Biodistribution of a Prosthetic Group (18F-FENMA) Conjugated to Cyclic RGD Peptides

“…LC-MS spectra were recorded on a LCQ DECA XP MAX instrument using electrospray ionization (ESI) or a Waters LCT-TOF (Instrument teknikk AS, Oslo, Norway) instrument (for high-resolution mass spectrometry (HRMS)) using a Phenomenex Luna (Teknolab) C18(2) column (20 mm × 2 mm, 3 µm), flow rate 0.6 mL/min with gradient 0-30% B. UV detection was in all instances at 214 and 254 nm. Synthesis of the tosylate precursor and labeling with [ 18 F]fluoride yielding O- (2-(2-[ 18 F]fluoroethoxy)ethyl)-Nmethylhydroxylamine (abbreviated 18 F-FENMA) was carried out as described previously (14). The cyclic RGD peptide NC100717, was supplied by GE Healthcare (Oslo, Norway) (16).…”

“…Recently, we reported a novel prosthetic group O-(2-(2-[ 18 F]fluoroethoxy)ethyl)-N-methylhydroxylamine ( 18 F-FENMA) utilizing the site-selective reactivity of the N-methylaminooxy functionalitywithpeptidesmodifiedwithaMichaelacceptor (14,15). Further extension of this approach is reported in this study using the RGD peptide 1 modified with either 4-[(E)-2-nitrovinyl-]benzoic acid or a 3-vinylsulfonylpropionyl group.…”

Site‐specific addition of an 18F‐N‐methylaminooxy‐containing prosthetic group to a vinylsulfone modified peptide

“…Recently, our group reported a new [ 18 F]prosthetic group based on the reactivity of the N‐ methylaminooxy functionality with Michael acceptors 10. Here, we report a further extension of the utility of this prosthetic group using the model peptide (vinylsulfonyl)acetyl‐Lys‐Gly‐Phe‐Gly‐Lys 6 .…”