technical-aspect-automated-synthesis-real-time-kinetic-evaluation

Technical Aspect of the Automated Synthesis and Real-Time Kinetic Evaluation of [<sup>11</sup>C]SNAP-7941

Positron emission tomography (PET) is an essential molecular imaging technique providing insights into pathways and using specific targeted radioligands ...

Medical University of Vienna

Ludwig Boltzmann Institute Applied Diagnostics

The melanin-concentrating hormone receptor 1 (MCHR1) has become an important pharmacological target, since it may be involved in various diseases, such as diabetes, insulin resistance, and obesity. Hence, a suitable positron emission tomography radiotracer for the in vivo assessment of the MCHR1 pharmacology is imperative. The current paper contrasts the extensive in vitro, in vivo, and ex vivo assessments of the radiotracers [F]FE@SNAP and [C]SNAP-7941 and provides comprehensive information about their biological and physicochemical properties. Furthermore, it examines their suitability for first-in-man imaging studies.

SNAPshots of the MCHR1: a Comparison Between the PET-Tracers [F]FE@SNAP and [C]SNAP-7941.

The tracer -Hydroxyephedrine ([[11C]HED) 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]HED and investigating the effect of the apparent molar activity (sum of HED 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]HED is easily applicable and reproducible. Moreover, it was shown that the administered apparent molar activities had a negligible effect on the imaging quality.

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

An intriguing target involved in several pathophysiological processes is the 18 kDa translocator protein (TSPO), of which exact functions remained elusive until now. A single nucleotide polymorphism in the  gene influences the binding affinity of endogenous and synthetic TSPO ligands by facilitating a lower-affinity conformation, which modifies a potential ligand binding site, ultimately leading to a binding profile classification according to each genotype. For instance, some clinical effects of the distinctive binding affinity profile of cholesterol toward the TSPO of individuals with different genotypes have been extensively discussed. Therefore, we conducted an investigation based on a radioligand binding assay, to determine the inhibition constants of some reported endogenous TSPO ligands (diazepam binding inhibitor and protoporphyrin IX), as well as synthetic ligands (disulfiram and derivatives). We observed no dependency of the polymorphism on the binding affinity of the evaluated endogenous ligands, whereas a high dependency on the binding affinity of the tested synthetic ligands was evident.

Article	Year
SNAPshots of the MCHR1: a Comparison Between the PET-Tracers [F]FE@SNAP and [C]SNAP-7941. Molecular imaging and biology : MIB : the official publication of the Academy of Molecular Imaging\| PubMed ID: 29948643	2019
Optimization of the Automated Synthesis of [11C]mHED-Administered and Apparent Molar Activities. Pharmaceuticals (Basel, Switzerland)\| PubMed ID: 30646635	2019
Binding Affinity of Some Endogenous and Synthetic TSPO Ligands Regarding the rs6971 Polymorphism. International journal of molecular sciences\| PubMed ID: 30699908	2019

Markus Mitterhauser

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