Comparison of two ¹⁸F-fluorinated glycopeptides for PET imaging of the functional liver mass

The non-invasive determination of the asialoglycoprotein receptor (ASGR) expression on liver tissue might be a predictive parameter helping to prevent severe liver diseases as well as liver failure after surgery and transplantation. Recently, we introduced [⁶⁸Ga]Ga-NODAGA-NonaLysan, which showed even a higher liver uptake as the gold standard [^99mTc]Tc-Galactosyl Serum Albumin. Here we describe the synthesis and evaluation of two ¹⁸F-labeled analogues, prepared using either a SiFA- or an AlF-labeling approach.

The two precursors could be produced in high purity (> 97%). Both labeling strategies allowed production of the radiopharmaceuticals in high radiochemical purity. The radiochemical yield was up to 58% d.c. for [¹⁸F]SiFA-NonaLysan and up to 71% d.c. for Al[¹⁸F]F-NOTA-6-Ahx-NonaLysan. In vitro evaluation showed high stability in PBS and human serum. Both compounds possessed nanomolar affinity for the ASGR (IC₅₀ = 0.9 ± 1.1 nM and 3.0 ± 2.1 nM, respectively). However, based on the design differences, Al[¹⁸F]F-NOTA-6-Ahx-NonaLysan showed a 100-fold lower logD as found for [¹⁸F]SiFA-NonaLysan. In consequence, the protein binding effect was higher for [¹⁸F]SiFA-NonaLysan, and the lipophilic character drastically affected the pharmacokinetic pattern. Initial liver uptake was higher for [¹⁸F]SiFA-NonaLysan (100% ID/g vs. 70% ID/g 10 min p.i.), but was accompanied by a quick organ washout and activity accumulation in the intestines. A much better activity retention was observed for Al[¹⁸F]F-NOTA-6-Ahx-NonaLysan. PET/MR imaging confirmed the differences in liver uptake, with a higher retention found for the latter. Based on the receptor function, both compounds are internalized and subsequently degraded. For Al[¹⁸F]F-NOTA-6-Ahx-NonaLysan, all radioactive liver metabolites found were more hydrophilic than the intact compound. For [¹⁸F]SiFA-NonaLysan, the contrary is the case, and almost all liver metabolites were more lipophilic. The hepatobiliary excretion of these metabolites prevents a stable activity retention in the hepatic tissue.

In this study, we successfully synthesized two new ¹⁸F-labeled radiopharmaceuticals targeting the ASGR. The in vivo evaluation revealed two different pharmacokinetic profiles. Extremely high uptake was found for [¹⁸F]SiFA-NonaLysan in the initial phase, followed by a quick organ washout. Al[¹⁸F]F-NOTA-6-Ahx-NonaLysan showed a lower but more stable activity retention in the liver, indicating advantageous imaging properties.