Optimization of the Automated Synthesis of [11C]mHED-Administered and Apparent Molar Activities.

Chrysoula Vraka,Markus Mitterhauser,Xiang Li,Marcus Hacker,Neydher Berroterán-Infante,Katharina Pallitsch,Anna Pillinger,Dietrich Beitzke,Maximilian Hohensinner,Cecile Philippe,Wolfgang Wadsak,Lukas Fetty,Tim Wollenweber,Verena Pichler

doi:10.3390/ph12010012

Abstract

The tracer [11C]meta-Hydroxyephedrine ([11C]mHED) is one of the most applied PET tracers for cardiac imaging, whose radiosynthesis was already reported in 1990. While not stated in the literature, separation difficulties and an adequate formulation of the product are well known challenges in its production. Furthermore, the precursor (metaraminol) is also a substrate for the norepinephrine transporter, and can therefore affect the image quality. This study aims at optimizing the synthetic process of [11C]mHED and investigating the effect of the apparent molar activity (sum of mHED and metaraminol) in patients and animals. The main optimization was the improved separation through reverse phase-HPLC by a step gradient and subsequent retention of the product on a weakly-cationic ion exchange cartridge. The µPET/µCT was conducted in ten rats (ischemic model) and the apparent molar activity was correlated to the VOI- and SUV-ratio of the myocardium/intra-ventricular blood pool. Moreover, nine long-term heart transplanted and five Morbus Fabry patients underwent PET and MRI imaging for detection of changes in the sympathetic innervation. In summary, the fully-automated synthesis and optimized purification method of [11C]mHED is easily applicable and reproducible. Moreover, it was shown that the administered apparent molar activities had a negligible effect on the imaging quality.

Highlights

The world health organization (WHO) estimates that almost 18 million people die of cardiovascular diseases (CVD) each year
Advantages of [11C]mHED are the metabolic resistance against the enzymes MAO and COMT, and in contrast to endogenous ligands, the high selectivity towards uptake-1, the low non-specific binding to the myocardium, the fast pharmacokinetics, as well as a continuous release and re-uptake by sympathetic nerves [5,6]
The methylation of metaraminol was highly reproducible in a mixture of DMF:DMSO as solvent, leading to a stable radiochemical yield of around 2–3 GBq. This yield was sufficient for 2–3 animals or at least 1 patient dose per production

Summary

Introduction

The world health organization (WHO) estimates that almost 18 million people die of cardiovascular diseases (CVD) each year. There is a high demand for a reliable imaging technique enabling the investigation of CVDs. One of the most frequently used positron emission tomography (PET) tracers in this regard is [11C]meta-hydroxyephedrine ([11C]mHED), known as 3-[(1R,2S)-1-hydroxy-2-([11C]methylamino)propyl]phenol, a false transmitter agent and a norepinephrine transporter (NET) substrate [3,4]. It has been described that [11C]mHED underlies the uptake-1 pathway of NET from the synaptic cleft to the cytoplasm of the sympathetic nerve terminal. Advantages of [11C]mHED are the metabolic resistance against the enzymes MAO (monoamine oxidase) and COMT (catechol-O-methyltransferase), and in contrast to endogenous ligands, the high selectivity towards uptake-1, the low non-specific binding to the myocardium, the fast pharmacokinetics, as well as a continuous release and re-uptake by sympathetic nerves [5,6]. [11C]mHED might be utilized in oncology for the diagnosis of adrenal tumors and metastasis [10,11]

Objectives

Results

Discussion

Conclusion