Facile synthesis and 18F-radiolabeling of α4ß1-specific LLP2A-aryltrifluoroborate peptidomimetic conjugates.

ABSTRACT

The peptidomimetic, LLP2A, is a specific, high-affinity ligand for α4ß1 integrin receptors. Previously, several PEGylated LLP2A conjugates were evaluated in vivo as imaging agents for the detection of lymphoma, leukemia, multiple myeloma and melanoma tumours via NIR-fluorescence, 111In-SPECT, and 64Cu- and 68Ga-PET imaging. Despite these successes, to date there is no report of an 18F-labeled LLP2A conjugate. Notably, fluorine-18 is a preferred radionuclide for PET imaging, yet its short half-life and general inactivity under aqueous conditions present challenges for peptide labeling. A simple method for labeling complex biomolecules can be achieved with arylboronic acids that readily capture aqueous [18F]-fluoride ion resulting in an 18F-labeled aryltrifluoroborate ([18F]-ArBF3-) radioprosthetic group. Herein, we present the first radiosynthesis of an 18F-labeled LLP2A conjugate by both one-step 18F-labeling and one-pot two-step 18F-labeling post-'click' conjugation of the 18F-alkynyl-ArBF3- prosthetic. Competition with a fluorescent conjugate of LLP2A demonstrated specific binding of the non-radioactive isotopolog ArBF3--PEG2-LLP2A to α4ß1 integrin-expressing MOLT-4 leukemia cells, as evidenced and confirmed by fluorescence microscopy. This work provides a key first step in the development of an expanding library of [18F]-R-BF3--LLP2A radiotracers for PET imaging.