Solid-phase synthesis and fluorine-18 radiolabeling of cycloRGDyK

Abstract

Solid-phase peptide synthesis, head-to-tail cyclization, and subsequent radiolabeling provided a reproducible, simple, rapid synthetic method to generate the cyclic peptide radiotracer cRGDyK([18F]FBA). Herein is reported the first on-resin cyclization and 18F-radiolabeling of a cyclic peptide (cRGDyK) in an overall peptide synthesis yield of 88% (cRGDyK(NH2)) and subsequent radiolabeling yield of 14 ± 2% (decay corrected, n = 4). This approach is generally applicable to the development of an automated process for the synthesis of cyclic radiolabeled peptides for positron emission tomography (PET).

Improved synthesis on solid phase of dithiocarbamic cRGD‐derivative and 99mTc‐radiolabelling

“…Altogether, results indicate that the best synthetic route for the preparation of this specific head‐to‐tail cyclic peptide is the one depicted in Scheme , whereby the fully protected cyclic peptide is generated on a 2‐chlorotrityl‐chloride resin. The yield after purification and lyophilization was comparable with that reported in previous works by Hassert et al (31%) and Davis et al (46%), as well as the one reported, only analytically, by Del Gatto et al (66%, using NovaSyn TGA by Novabiochem) for the preparation of the analogue c [RGDfK].…”

“…Most methods also suffer the racemization of the C‐terminal residue or aspartimide formation, and formation of tetramethyl‐guanidinium derivatives . To partly overcome these problems, the solubility difficulties often encountered with fully protected peptides and to avoid lengthy intermediate purifications, on‐resin cyclisation and lysine functionalization approaches have been devised and reported . However, even if solid‐phase cyclisation has represented a step forward compared with the one in solution to circumvent cyclo‐dimerization and/or oligomerization side reactions, it does not always completely solve the problem .…”

“…Among these, the c [RGDfK] peptide is frequently employed. For this purpose, the Lys side chain is conjugated to a bifunctional chelating agent suitable for the coordination and stabilization of radionuclides for both SPECT/PET imaging and theranostic use . For these reasons, it is of considerable interest to find a rapid, efficient, and practically scalable protocol for the synthesis of cyclic peptides and the introduction of radio‐tracers.…”

Fully automated peptide radiolabeling from [18F]fluoride

“…[50][51][52][53][54][55] The yield obtained for cRGDyK([ 18 F]FPy) was also similar to the previously reported manual solid phase radiolabeling of cRGDyK with 6-[ 18 F]uorobenzoic acid (14 AE 2% yield in 90 minutes). 42 Overall, using the ELIXYS FLEX/CHEM® radiosynthesizer was faster, with a total synthesis time under a 100 minutes including HPLC purication, and provided similar radiochemical yields.…”

Identification, Characterization, and Optimization of Integrin αvβ6-Targeting Peptides from a One-Bead One-Compound (OBOC) Library: Towards the Development of Positron Emission Tomography (PET) Imaging Agents

“…All peptides were radiolabeled with [ 18 F]fluorobenzoic acid ([ 18 F]FBA) on resin following our well-established solid-phase radiolabeling protocols [16,20,37]. Briefly, [ 18 F]fluoride was reacted with ethyl-4-(trimethylammonium triflate)benzoate in the presence of 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo [8.8.8]hexacosane (Kryptofix TM [K2.2.2], (Sigma Aldrich, St. Louis, MO, USA) and potassium carbonate at 100 °C in dimethylsulfoxide (DMSO) for 15 min, followed by saponification of the ethyl ester protect group to yield [ 18 F]FBA.…”