Initial Evaluation of AF78: a Rationally Designed Fluorine-18-Labelled PET Radiotracer Targeting Norepinephrine Transporter

Xinyu Chen,Naoko Nose,Kazuhiro Koshino,Takahiro Higuchi,Michael Decker,Yusuke Yagi,Alexander Fritz,Hiroyuki Kimura,Rudolf A Werner,Steven P Rowe

doi:10.1007/s11307-019-01407-5

Abstract

PurposeTaking full advantage of positron emission tomography (PET) technology, fluorine-18-labelled radiotracers targeting norepinephrine transporter (NET) have potential applications in the diagnosis and assessment of cardiac sympathetic nerve conditions as well as the delineation of neuroendocrine tumours. However, to date, none have been used clinically. Drawbacks of currently reported radiotracers include suboptimal kinetics and challenging radiolabelling procedures.ProceduresWe developed a novel fluorine-18-labelled radiotracer targeting NET, AF78, with efficient one-step radiolabelling based on the phenethylguanidine structure. Radiosynthesis of AF78 was undertaken, followed by validation in cell uptake studies, autoradiography, and in vivo imaging in rats.Results[18F]AF78 was successfully synthesized with 27.9 ± 3.1 % radiochemical yield, > 97 % radiochemical purity and > 53.8 GBq/mmol molar activity. Cell uptake studies demonstrated essentially identical affinity for NET as norepinephrine and meta-iodobenzylgaunidine. Both ex vivo autoradiography and in vivo imaging in rats showed homogeneous and specific cardiac uptake.ConclusionsThe new PET radiotracer [18F]AF78 demonstrated high affinity for NET and favourable biodistribution in rats. A structure-activity relationship between radiotracer structures and affinity for NET was revealed, which may serve as the basis for the further design of NET targeting radiotracers with favourable features.

Highlights

In recent years, the development of positron emission tomography (PET) technology has increasingly been explored for cardiac and other applications due to its higher spatial and temporal resolution compared to single photon emission computed tomography (SPECT) [1]
A structure-activity relationship between radiotracer structures and affinity for norepinephrine transporter (NET) was revealed, which may serve as the basis for the further design of NET targeting radiotracers with favourable features
The development of positron emission tomography (PET) technology has increasingly been explored for cardiac and other applications due to its higher spatial and temporal resolution compared to single photon emission computed tomography (SPECT) [1]

Summary

Introduction

The development of positron emission tomography (PET) technology has increasingly been explored for cardiac and other applications due to its higher spatial and temporal resolution compared to single photon emission computed tomography (SPECT) [1]. Typical examples include (1) 6-[18F]fluorodopamine, which was first reported more than 20 years ago [8, 9]; (2) [18F]meta-fluorobenzylguanidine ([18F]MFBG), which is the fluoride analogue of the only clinically used NET radiotracer [123I]meta-iodobenzylguanidine ([123I]MIBG), a singlephoton emitting compound [10, 11]; (3) 1-(3-bromo-4-(3[18F]fluoropropoxy)benzyl)guanidine ([18F]LMI1195), which shares comparable in vitro and in vivo characteristics as [123I]MIBG due to a common benzylguanidine core structure [12,13,14]; and (4) 4-[18F]fluoro-3hydroxyphenethylguanidine ([18F]4F-MHPG) and its isomer 3-[18F]fluoro-4-hydroxyphenethylguanidine ([18F]3FPHPG), which have shown unique slow uptake kinetics due to their phenethylguanidine core structures [15, 16] (Fig. 1) Among these radiotracers, [18F]LMI1195 [17] and [18F]4F-MHPG/3F-PHPG [18, 19] have been used mainly for cardiac sympathetic innervation imaging and have shown acceptable safety and favourable properties in clinical phase 1 trials

Objectives

Methods

Results

Discussion

Conclusion