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Molecular Imaging and Biology

Species-Specific Hepatic Uptake of [64Cu]Cu-EOB-NOTA, A Newly Designed Hepatospecific PET Agent

  • Open Access
  • 30-04-2025
  • Research Article
Published in:
Authors
Jinda Fan
Bijja Janaki Ramulu
Christiane L. Mallett
Legend E. Kenney
Nathan Kauffman
Tapas Bhattacharyya
Maryam Sabbaghan
Satyendra Singh
Kurt R. Zinn
Erik M. Shapiro
Published in
Molecular Imaging and Biology | Issue 3/2025

Abstract

Purpose

Measuring hepatic flux rates of transportable substrates has the potential for assessing liver function. PET imaging of a PET-enabled substrate may provide a more straightforward measurement of time-dependent substrate concentration through the liver than MRI using an MRI contrast agent. Here we synthesized and evaluated the hepatobiliary transport of a new hepatospecific PET agent designed for stable Cu2+ chelation and transport by hepatic OATPs, [64Cu]Cu-EOB-NOTA.

Procedures

EOB-NOTA was synthesized, its two enantiomers separated by chiral HPLC, and individually radiolabeled with [64Cu]Cu2+. Cocktails of each enantiomer of [64Cu]Cu-EOB-NOTA and Gd-EOB-DTPA were formulated for simultaneous PET/MRI imaging of hepatic flux by PET and MRI. Two mouse models were evaluated: wild-type mice and mice expressing only human hepatic OATPs.

Results

In wild-type mice, [64Cu]Cu-EOB-NOTA hepatic influx and efflux was high, but slower compared to Gd-EOB-DTPA. Neither enantiomer of [64Cu]Cu-EOB-NOTA exhibited detectable transport into the liver in mice expressing human OATPs. This was validated by waste clearance studies and in vitro uptake assays in cells engineered to express rodent and human OATPs.

Conclusion

[64Cu]Cu-EOB-NOTA exhibited no detectable hepatic uptake by transgenic mice expressing human hepatic transporters. This finding was surprising given the efficient transport of the structurally similar metal chelate Gd-EOB-DTPA, and underscores challenges in the design of imaging molecular probes, including poor predictability for hepatic transport, and the value of validating new agents in mice expressing human hepatic transporters.
Title
Species-Specific Hepatic Uptake of [64Cu]Cu-EOB-NOTA, A Newly Designed Hepatospecific PET Agent
Authors
Jinda Fan
Bijja Janaki Ramulu
Christiane L. Mallett
Legend E. Kenney
Nathan Kauffman
Tapas Bhattacharyya
Maryam Sabbaghan
Satyendra Singh
Kurt R. Zinn
Erik M. Shapiro
Publication date
30-04-2025
Publisher
Springer International Publishing
Published in
Molecular Imaging and Biology / Issue 3/2025
Print ISSN: 1536-1632
Electronic ISSN: 1860-2002
DOI
https://doi.org/10.1007/s11307-025-02009-0
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