Research & Teaching Faculty

tBu4octapa-alkyl-NHS for Metalloradiopeptide Preparation

TitletBu4octapa-alkyl-NHS for Metalloradiopeptide Preparation
Publication TypeJournal Article
Year of Publication2020
AuthorsLi, LLee Lee, Kuo, H-T, Wang, X, Merkens, H, Colpo, N, Radchenko, V, Schaffer, P, Lin, K-S, Bénard, F, Orvig, C
JournalDalton Trans.
Pagination7605 - 7619
Date Published05/2020

The peptide is an important class of biological targeting molecule; herein{,} a new bifunctional octadentate non-macrocyclic H4octapa{,} tBu4octapa-alkyl-NHS{,} which is compatible with solid-phase peptide synthesis and thus useful for radiopeptide preparation{,} has been synthesized. To preserve denticity{,} the alkyl-N-hydroxylsuccinimide linker was covalently attached to the methylene-carbon on one of the acetate arms{,} yielding a chiral carbon center. According to density-functional theory (DFT) calculations using [Lu(octapa-alkyl-benzyl-ester)]- as a simulation model{,} the chirality has minimal effects on the complex geometry; regardless of the S-/R-stereochemistry{,} DFT calculations revealed two possible geometric isomers{,} distorted bicapped trigonal antiprism (DBTA) and distorted square antiprism (DSA){,} due to the asymmetry in the chelator. To evaluate the biological behavior of the new bifunctionalization{,} two well-studied PSMA (prostate-specific membrane antigen)-targeting peptidomimetics of varying hydrophobicity were chosen as proof-of-principle targeting vector molecules. Radiolabeling both bioconjugates with lutetium-177 was highly efficient at room temperature in 15 min at micromolar chelator concentration pH = 7. Both the in vitro serum challenge and the lanthanum(III) challenge studies revealed complex lability{,} and notably{,} progressive bone accumulation was only observed with the more hydrophobic linker (i.e. H4octapa-alkyl-PSMA617). This in vivo result informs potential alterations exerted by the linker on the complex geometry and stability{,} with an appropriate biological targeting vector adopted for such evaluations.

Refereed DesignationRefereed