Conference Presentation (After Call)

FZJ-2024-04011

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Convenient preparation of 18F-labeled human insulin by Pd-catalyzed S-arylation

Humpert, S. (Corresponding author)FZJ* ; Neumaier, B.FZJ* ; Zlatopolskiy, B.FZJ*

2022

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Please use a persistent id in citations: doi:10.1016/S0969-8051(22)00259-1

Abstract: Objective: Insulin is a peptide hormone that is produced andsecreted by pancreatic ß-cells. Apart from its well-known role forthe regulation of blood glucose homeostasis, insulin is consideredto be an important modulator of certain brain functions, includingfeeding behavior and cognition, although the mechanisms of insulin transfer into the central nervous system (CNS) remain unclear. Whilethe preparation of several radiolabeled insulin derivatives has beenreported, their application as probes for in vivo PET studies is hamperedby low yields and low molar activities due to inefficient andlengthy production routes. Herein we report a rapid and efficientprocedure for the preparation of high molar activity insulin selectivelylabeled at the Lys29 residue in the B-chain.Methods: Radiolabeling of thiol-modified insulin was performedby S-arylation with 2-[18F]Fluoro-5-iodopyridine ([18F]FIPy) in MeCN/phosphate buffer at 37°C for 3 minutes in the presence of XantphosPd G3 catalyst as recently reported [1]. The product was isolated byRP HPLC with a conventional C18 column. The appropriate substratefor S-conjugation was prepared as follows. Treatment of humaninsulin with N-hydroxysuccimidyl ester of S-Trt protected 4-mercaptobutyricacid in DMF/TRIS buffer (pH = 10.5) afforded Lysb29acylated insulin, which was deprotected with TFA/TIS/H2O (75:20:5).[18F]FIPy was prepared from the corresponding DABCO precursorusing the “minimalist” radiofluorination protocol and isolated by SPEor fast HPLC (7 min).Results: Insulin containing an SH-tag at the Lysb29 residue wasprepared in 14% yield over two steps. Subsequent conjugation withSPE-isolated [18F]FIPy afforded the radiolabeled insulin derivative ina RCY of 11% over two steps. In contrast, conjugation of HPLC-isolated[18F]FIPy with only 100–200 nmol thiol-modified insulin yielded thedesired 18F-fluorinated product in RCYs of 35 ± 4% (n=4) with highradiochemical and chemical purity within 60 min. The suitability forin vivo PET studies was exemplified by preparation of 1.2 GBq radiolabeledinsulin with a molar activity of 100 GBq/µmol starting from6 GBq [18F]F−. Conclusion: Highly efficient production of 18F-labeled insulin fromtiny precursor amounts underlines the high potential of Pd-catalyzedS-arylation with [18F]FIPy for radiolabeling of sensitive biomolecules.

Note: This work was supported by the DFG grant ZL 65/4-1.

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Contributing Institute(s):

1. Nuklearchemie (INM-5)

Research Program(s):

1. 5253 - Neuroimaging (POF4-525) (POF4-525)

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