In Vivo Veritas: ¹⁸F-Radiolabeled Glycomimetics Allow Insights into the Pharmacological Fate of Galectin-3 Inhibitors

Abstract

Glycomimetic drugs have attracted increasing interest as unique targeting vectors or surrogates for endogenous biomolecules. However, it is generally difficult to determine the in vivo pharmacokinetic profile of these compounds. In this work, two galectin-3 inhibitors were radiolabeled with fluorine-18 and used as surrogate PET tracers of TD139 and GB1107. Both compounds are promising drugs for clinical applications. In vivo evaluation revealed that both surrogates strongly differed with respect to their biodistribution profile. The disaccharide (TD139 surrogate) was rapidly eliminated from blood while the monosaccharide (GB1107 surrogate) showed no sign of excretion. The data obtained allowed us to infer the different in vivo fate of TD139 and GB1107 and rationalize how different administration routes could boost efficacy. Whereas the fast excretion profile of the TD139 surrogate indicated that systemic application of disaccharides is unfavorable, the extended biological half-life of the GB1107 surrogate indicated that systemic administration is possible for monosaccharides.

Protecting-Group-Free Synthesis of GB1107: An Orally Active Galectin-3 Antagonist

“…In the case of galectin inhibitors, the group of Nilsson reported Clog D values at pH 7.4 of TD139 (1) and GB1107 (2). 13 Clog D refers to a calculated log P at a given pH. Herein, we wish to report the log P of compound 1 using a method based on 19 F NMR spectroscopy.…”

“…The mixture was filtered, concentrated under reduced Figure 2 Log P determination method and lipophilicity of galectin inhibitor TD139 (1; GB0139) F 1 H NMR (500 MHz, acetone-d 6 ):  = 5.18 (t, J = 1.6 Hz, 1 H, H-1), 4.73 (d, J = 5.9 Hz, 1 H, OH-4), 4.41 (d, J = 6.9 Hz, 1 H, OH-2), 4.34-4.30 (m, 2 H, H-6endo; H-5), 4.29 (dddd, J = 5.8, 4.0, 1.1, 0.5 Hz, 1 H, H-4), 3.91 (dq, J = 5.6, 1.4 Hz, 1 H, H-3), 3.62 (dt, J = 7.0, 1.7 Hz, 1 H, H-2), 3.51 (dddd, J = 7.1, 5.2, 1.3, 0.5 Hz, 1 H, H-6exo). 13 Deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1yl]-1-thio-/-D…”

“…13 C{H 1 } NMR (126 MHz, CD 3 OD):  = 152.9 (ddd, J = 247.9, 10.3, 2.4 Hz, 2 C, Ar), 145.6 (q, J = 2.5 Hz, 1 C, triazole), 140.5 (dt, J = 250.5, 15.4 Hz, 1 C, Ar), 135.6 (s, 1 C, Ar), 132.4 (s, 2 C, Ar), 130.0 (s, 2 C, Ar), 128.9 (td, J = 9.2, 9.0, 4.5 Hz, 1 C), 128.4 (s, 1 C, Ar), 122.8 (s, 1 C, triazole), 110.78 (dd, J = 17.5, 5.6 Hz, 2 C, Ar), 91.3 (s, 1 C, C-1), 80.9 (s, 1 C, C-5), 69.5 (s, 1 C, C-4), 69.2 (s, 1 C, C-3), 68.0 (s, 1 C, C-2), 62.3 (s, 1 C, C-6) 19. F NMR (470 MHz, CD 3 OD):  = -136.6 (dd, J = 19.9, 8.4 Hz, 2 F, ArF), -164.8 (tt, J = 19.9, 6.7 Hz, 1 F, ArF).HRMS (ESI): m/z [M + H] + calcd for C 20 H 19 F 3 N 3 O 4 S + : 454.1043; found: 454.1034.…”

Interaction between Galectin-3 and Integrins Mediates Cell-Matrix Adhesion in Endothelial Cells and Mesenchymal Stem Cells

“…Gal-3 binds not only β-galactoside-capped glycans displayed on the surface of glycoproteins, but it can also bind synthetic carbohydrates and glycomimetics, which can be produced in relatively large quantities. The simplest ligands are represented by disaccharides LacNAc (Galβ1,4GlcNAc), LacdiNAc (GalNAcβ1,4GlcNAc), or thiodigalactoside (Galβ1,1-S-Gal), which can be attached to various biocompatible carriers [ 17 , 18 ] or derivatized [ 19 , 20 ]. In earlier studies, poly-LacNAc-based oligosaccharide ligands were bound, e.g., to a scaffold of bovine serum albumin [ 21 ], or LacdiNAc was attached to hydrophilic N -(2-hydroxypropyl) methacrylamide (HPMA) copolymers and used in the form of a glyconanomaterial [ 11 ].…”

Sequence‐Defined Heteromultivalent Precision Glycomacromolecules Bearing Sulfonated/Sulfated Nonglycosidic Moieties Preferentially Bind Galectin‐3 and Delay Wound Healing of a Galectin‐3 Positive Tumor Cell Line in an In Vitro Wound Scratch Assay

“…[ 48 ] In addition, thiodigalactoside analogs substituted with hydrophobic groups at the 3‐positions have shown significant selectivity and binding to galectin‐3 in the nm range. [ 47–56 ] For example, TD139, is currently in clinical trials for treating idiopathic pulmonary fibrosis. [ 57 ]…”