68Ga-Labeled TRAP-Based Glycoside Trimers for Imaging of the Functional Liver Reserve

The exclusive asialoglycoprotein receptor (ASGR) expression on hepatocytes makes it an attractive target for imaging of the functional liver reserve. Here, we present a set of TRAP-based glycoside trimers and evaluate their imaging properties compared to the gold standard [99mTc]Tc-GSA. The click-chemistry-based synthesis approach provided easy access to trimeric low-molecular-weight compounds. Labeling with 68Ga was carried out in high radiochemical yields (>99%). Complexes showed high stability and hydrophilicity. Protein binding ranged between 10 and 25%. Highest binding affinity (IC50) and best liver accumulation were found for [68Ga]Ga-T3N3, followed by [68Ga]Ga-T3G3 and [68Ga]Ga-T0G3. Rapid elimination from the rest of the body resulted in excellent target-to-background ratios. Our studies confirmed that high ASGR uptake depends on the correct spacer design and that N-acetylgalactosamine improves targeting properties in vivo. Thus, [68Ga]Ga-T3N3 represents a new low-molecular-weight radiopharmaceutical with pharmacokinetics similar to those of [99mTc]Tc-GSA.