Molecular Imaging-Derived Biomarker of Cardiac Nerve Integrity — Introducing High NET Affinity PET Probe 18F-AF78

Xinyu Chen, Rudolf A. Werner, Kazuhiro Koshino, Naoko Nose, Saskia Mühlig, Steven P. Rowe, Martin G. Pomper, Constantin Lapa, Michael Decker, Takahiro Higuchi

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Radiolabeled agents that are substrates for the norepinephrine transporter (NET) can be used to quantify cardiac sympathetic nervous conditions and have been demonstrated to identify high-risk congestive heart failure (HF) patients prone to arrhythmic events. We aimed to fully characterize the kinetic profile of the novel 18F-labeled NET probe AF78 for PET imaging of the cardiac sympathetic nervous system (SNS) among various species. Methods: 18F-AF78 was compared to norepinephrine (NE) and established SNS radiotracers by employing in vitro cell assays, followed by an in vivo PET imaging approach with healthy rats, rabbits and nonhuman primates (NHPs). Additionally, chase protocols were performed in NHPs with NET inhibitor desipramine (DMI) and the NE releasing stimulator tyramine (TYR) to investigate retention kinetics in cardiac SNS. Results: Relative to other SNS radiotracers, 18F-AF78 showed higher transport affinity via NET in a cell-based competitive uptake assay (IC50 0.42 ± 0.14 µM), almost identical to that of NE (IC50, 0.50 ± 0.16 µM, n.s.). In rabbits and NHPs, initial cardiac uptake was significantly reduced by NET inhibition. Furthermore, cardiac tracer retention was not affected by a DMI chase protocol but was markedly reduced by intermittent TYR chase, thereby suggesting that 18F-AF78 is stored and can be released via the synaptic vesicular turnover process. Computational modeling hypothesized the formation of a T-shaped π-π stacking at the binding site, suggesting a rationale for the high affinity of 18F-AF78. Conclusion: 18F-AF78 demonstrated high in vitro NET affinity and advantageous in vivo radiotracer kinetics across various species, indicating that 18F-AF78 is an SNS imaging agent with strong potential to guide specific interventions in cardiovascular medicine.

Original languageEnglish
Pages (from-to)4446-4458
Number of pages13
JournalTheranostics
Volume12
Issue number9
DOIs
Publication statusPublished - 2022
Externally publishedYes

Keywords

  • cardiac innervation imaging
  • nonhuman primates
  • norepinephrine transporter
  • radiotracer kinetics
  • sympathetic nervous system
  • T-shaped π-π stacking

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Pharmacology, Toxicology and Pharmaceutics (miscellaneous)

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