[68Ga]NOTA-Galactosyl Human Serum Albumin: a Tracer for Liver Function Imaging with Improved Stability

Abstract

PurposeNon-invasive techniques allowing quantitative determination of the functional liver mass are of great interest for patient management in a variety of clinical settings. Recently, we presented [68Ga]DTPA-GSA to target the hepatic asialoglycoprotein receptor for this purpose. Here, we introduce [68Ga]NOTA-GSA to improve metabolic stability of the radiopharmaceutical and compare the imaging properties with [68Ga]DTPA-GSA.ProceduresLabeling of the compounds was carried out at room temperature using 1.9 M sodium acetate as buffer. For quality control, thin-layer, high-performance liquid, and size exclusion chromatographies were used. Metabolic stability was studied in rat and human serums. For in vivo evaluation, Fischer rats were scanned by positron emission tomography and magnetic resonance imaging and subsequently sacrificed for biodistribution studies. Time activity curves (TACs) for heart and liver were generated and corresponding parameters (T50, T90, LHL15, HH15) were calculated.Results[68Ga]NOTA-GSA can be produced in high radiochemical yield and purity (>95 %) within 15 min. Stability studies revealed almost no metabolite formation over the 2-h observation period. Analysis of the TACs showed comparable results for most of the investigated parameters. The only significant difference was found in the T90 value, where [68Ga]NOTA-GSA showed slower uptake in comparison with 68Ga-DTPA-GSA (123 ± 10 vs. 89 ± 3 s, p < 0.01).Conclusions[68Ga]NOTA-GSA showed a significant increase of the metabolic stability and in most organs lower background activity. However, comparison of LHL15 and HH15 indicates that the increased stability did not further improve the diagnostic value. Thus, [68Ga]NOTA-GSA and [68Ga]DTPA-GSA can be used equivalent for imaging hepatic function with positron emission tomography.

Metal-Based Complexes as Pharmaceuticals for Molecular Imaging of the Liver

“…For example, IDA is a small, tridendate ligand forming biscomplexes with Ga(III) [209] and Gd(III) [41], which have been reported to exhibit low stability, while the 99m Tc compounds are sufficiently stable [141]. Therefore, adaptation of the chelator is often necessary, e.g., from DTPA-GSA for 99m Tc to NOTA-GSA for 68 Ga [215].…”

“…While DTPA-GSA is a suitable ligand for 99m Tc, 68 Ga-DTPA-GSA has shown specific liver accumulation but poor stability in vivo [192]. The stability could be sufficiently improved by exchanging the chelator DTPA with the well-known 68 Ga chelator NOTA (Figure 7) [215]. A similar attempt was undertaken with NOTA-conjugated neolactosylated albumin (LSA), which exhibits 64% hepatic uptake when labeled with 68 Ga [216].…”

Triantennary GalNAc Molecular Imaging Probes for Monitoring Hepatocyte Function in a Rat Model of Nonalcoholic Steatohepatitis

“…Another hindrance is the lack of an animal model that recapitulates the complete NASH phenotype, including obesity and impaired glucose metabolism. [12][13][14][15][16][17][18] We overcome both challenges in the present study by developing imaging probes that selectively bind hepatocyte-specific asialoglycoprotein receptor (ASGPR), whose expression falls during development of liver fibrosis [19,20] and inflammatory processes, [21] and by creating a new rat model of NASH progression that recapitulates the obesity and insulin resistance of the disease, in which ASGPR can be monitored in vivo using our imaging probes in combination with positron emission tomography (PET).…”

“…Other described ASGPR-binding probes for PET imaging of further liver diseases rely on -d-galactose (d-Gal) [25][26][27] to increase affinity for ASGPR and these probes were conjugated to human serum albumin (HSA) to prolong half-life in blood circulation. [18,20,26,27] A few other approaches to use molecular tracers in nonalcoholic fatty liver (NAFLD) imaging using tryptophan-rich sensory protein, Integrin v 3 or GSA receptors have been attempted but the animal mouse models used in these studies were not clinically translatable to humans. [28] We describe herein a method to overcome the abovementioned specificity problems by developing a series of bifunctional chemical imaging probes that selectively bind to hepatocyte specific ASGPR and to study the receptor decrease during development of liver fibrosis in a new rat model of NASH by PET imaging and fluorescence tomography.…”

Development of single vial kits for preparation of 68Ga‐labelled hexavalent lactoside for PET imaging of asialoglycoprotein receptor

“…Due to the long synthesis steps and the instability of NGA, another ASGPR probe, the 99m Tc‐labeled LSA (neolactosyl HSA), was synthesized by simply conjugating commercially available lactose to HSA through reductive amination . Besides 99m Tc, glycosylated HSA was labeled for SPECT or PET imaging with various radioisotopes, including In‐111, I‐125/131, Ga‐67/68, and F‐18 . Although albumin‐based ASGPR‐targeted probes have been extensively evaluated, their application is limited by the regulations of biological products.…”