Evaluation of the Enantiomer Specific Biokinetics and Radiation Doses of [(18)F]Fluspidine-A New Tracer in Clinical Translation for Imaging of σ₁ Receptors.

Mathias Kranz,Marianne Patt,Swen Hesse,Steffen Fischer,Bernhard Wünsch,Winnie Deuther-Conrad,Nathanael Wüst,Cornelius Donat,Philipp Meyer,Osama Sabri,Jörg Steinbach,Bernhard Sattler,Peter Brust

doi:10.3390/molecules21091164

Abstract

The enantiomers of [18F]fluspidine, recently developed for imaging of σ1 receptors, possess distinct pharmacokinetics facilitating their use in different clinical settings. To support their translational potential, we estimated the human radiation dose of (S)-(−)-[18F]fluspidine and (R)-(+)-[18F]fluspidine from ex vivo biodistribution and PET/MRI data in mice after extrapolation to the human scale. In addition, we validated the preclinical results by performing a first-in-human PET/CT study using (S)-(−)-[18F]fluspidine. Based on the respective time-activity curves, we calculated using OLINDA the particular organ doses (ODs) and effective doses (EDs). The ED values of (S)-(−)-[18F]fluspidine and (R)-(+)-[18F]fluspidine differed significantly with image-derived values obtained in mice with 12.9 μSv/MBq and 14.0 μSv/MBq (p < 0.025), respectively. A comparable ratio was estimated from the biodistribution data. In the human study, the ED of (S)-(−)-[18F]fluspidine was calculated as 21.0 μSv/MBq. Altogether, the ED values for both [18F]fluspidine enantiomers determined from the preclinical studies are comparable with other 18F-labeled PET imaging agents. In addition, the first-in-human study confirmed that the radiation risk of (S)-(−)-[18F]fluspidine imaging is within acceptable limits. However, as already shown for other PET tracers, the actual ED of (S)-(−)-[18F]fluspidine in humans was underestimated by preclinical imaging which needs to be considered in other first-in-human studies.

Highlights

The existence of various tissues of the sigma opioid receptor (σ) was postulated first by Martin et al in 1976 [1]; nowadays it has been proven to be a non-opioid receptor (Sigma Non-OpioidIntracellular Receptor 1; σ1 receptor)
We report on the dosimetry and biodistribution of both enantiomers of the σ1 receptor ligand [18 F]fluspidine based on in vivo and ex vivo data from mice which we obtained by the dynamic hybrid positron emission tomography (PET)/MR imaging method as well as by an organ harvesting study
The time-dependent radioactive data for the animal and human studies was acquired with three different techniques. (i) The mice were scanned in a preclinical small animal PET/MRI while the (ii) human study was performed on a clinical PET/CT system

Summary

Introduction

This receptor plays an important role in the cellular functions associated with the endocrine, immune, and nervous systems; the physiological function of the σ1 receptor is not yet fully understood [2]. This protein interacts with a variety of psychotomimetic drugs, including cocaine and amphetamines. The binding potential (BPnd) of (R)-(+)-[18 F]fluspidine is 5- to 10-fold higher in comparison to (S)-(−)-[18 F]fluspidine in σ1 -rich areas of the porcine brain [9], most probably due to differences in their affinity towards σ1 receptors ((R)-(+)-[18 F]fluspidine: Ki = 0.57 nM; (S)-(−)-[18 F]fluspidine: Ki = 2.3 nM; [10]) These preclinical data indicated a suitability of both enantiomers of [18 F]fluspidine for different clinical issues. For the first-in-human investigation of σ1 receptors in brain we have chosen (S)-(−)-[18 F]fluspidine as the enantiomer with the faster pharmacokinetics for reasons of feasibility in clinical routine (German clinical trial register ID: DRKS00008321)

Methods

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Discussion

Conclusion