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3-18F-fluoropropane-1-thiol and 18F-PEG4-1-thiol: Versatile prosthetic groups for radiolabeling maleimide functionalized peptides.

ABSTRACT: The efficient radiosynthesis of biomolecules utilizing minute quantities of maleimide substrate is important for availability of novel peptide molecular imaging agents. We evaluated both 3-18F-fluoropropane-1-thiol and 2-(2-(2-(2-18F-fluoroethoxy)ethoxy)ethoxy)ethane-1-thiol (18F-fluoro-PEG4 thiol) as prosthetic groups for radiolabeling under physiological conditions. The precursor employed a benzoate for protection of the thiol and an arylsulfonate leaving group. The radiofluorination was fully automated on an Eckert & Ziegler synthesis system using standard Kryptofix222/K2CO3 conditions. In order to minimize the amount of biological molecule required for subsequent conjugation, the intermediates, S-(3-18F-fluoropropyl) benzothioate and 18F-fluoro-PEG4 benzothioate, were purified by HPLC. The intermediates were isolated from the HPLC in yields of 37-47% and 28-35%, respectively, and retrieved from eluate using solid phase extraction. Treatment of the benzothioates with sodium methoxide followed by acetic acid provided the free thiols. The desired maleimide substrate in acetonitrile or phosphate buffer was then added and incubated at room temperature for 15?min. The final radiolabeled bioconjugate was purified on a separate HPLC or NAP-5 column. Maleimides utilized for the coupling reaction included phenyl maleimide, an Evans Blue maleimide derivative, a dimeric RGDfK maleimide (E[c(RGDfK)]2), two aptamer maleimides, and PSMA maleimide derivative. Isolated radiochemical yields (non-decay corrected) of maleimide addition products based on starting 18F-fluoride ranged from 6 to 22% in a synthesis time of about 90?min. 18F-thiol prosthetic groups were further tested in vivo by conjugation to E[c(RGDfK)]2 maleimide in a U87MG xenograft model. PET studies demonstrated similar tumor accumulation of both prosthetic groups. 18F-fluoro-PEG4-S-E[c(RGDfK)]2 displayed a somewhat favorable pharmacokinetics compared to 18F-fluoropropyl-S-E[c(RGDfK)]2. Bone uptake was low for both indicating in vivo stability.

SUBMITTER: Jacobson O

PROVIDER: S-EPMC6983705 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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3-18F-fluoropropane-1-thiol and 18F-PEG4-1-thiol: Versatile prosthetic groups for radiolabeling maleimide functionalized peptides.

Jacobson Orit O Wang Zhantong Z Yu Guocan G Ma Ying Y Chen Xiaoyuan X Kiesewetter Dale O DO

Bioorganic & medicinal chemistry 20190805 19

The efficient radiosynthesis of biomolecules utilizing minute quantities of maleimide substrate is important for availability of novel peptide molecular imaging agents. We evaluated both 3-18F-fluoropropane-1-thiol and 2-(2-(2-(2-18F-fluoroethoxy)ethoxy)ethoxy)ethane-1-thiol (18F-fluoro-PEG4 thiol) as prosthetic groups for radiolabeling under physiological conditions. The precursor employed a benzoate for protection of the thiol and an arylsulfonate le ...[more]

PMID: 31402203

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Dataset Information

3-18F-fluoropropane-1-thiol and 18F-PEG4-1-thiol: Versatile prosthetic groups for radiolabeling maleimide functionalized peptides.

Publications

3-<sup>18</sup>F-fluoropropane-1-thiol and <sup>18</sup>F-PEG<sub>4</sub>-1-thiol: Versatile prosthetic groups for radiolabeling maleimide functionalized peptides.

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