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

CBmed GmbH - Center for Biomarker Research in Medicine

About 10% of patients with neurofibromatosis type 1 (NF-1) develop malignant peripheral nerve sheath tumours (MPNST) mostly arising in plexiform neurofibroma (PN); 15% of MPNST arise in children and adolescents. 2-[ F]fluoro-2-deoxy-d-glucose ([ F]FDG)-PET (where PET is positron emission tomography) is a sensitive method in differentiating PN and MPNST in symptomatic patients with NF-1. This study assesses the value of [ F]FDG-PET imaging in detecting malignant transformation in symptomatic and asymptomatic children with PN.

Monitoring of plexiform neurofibroma in children and adolescents with neurofibromatosis type 1 by [ F]FDG-PET imaging. Is it of value in asymptomatic patients?

The MCHR1 is involved in the regulation of energy homeostasis and changes of the expression are linked to a variety of associated diseases, such as diabetes and adiposity. The study aimed at the in vitro and in vivo evaluation of [C]SNAP-7941 and [F]FE@SNAP as potential PET-tracers for the MCHR1. Competitive binding studies with non-radioactive derivatives and small-animal PET/CT and MRI brain studies were performed under baseline conditions and tracer displacement with the unlabelled MCHR1 antagonist (±)-SNAP-7941. Binding studies evinced high binding affinity of the non-radioactive derivatives. Small-animal imaging of [C]SNAP-7941 and [F]FE@SNAP evinced high tracer uptake in MCHR1-rich regions of the ventricular system. Quantitative analysis depicted a significant tracer reduction after displacement with (±)-SNAP-7941. Due to the high binding affinity of the non-labelled derivatives and the high specific tracer uptake of [C]SNAP-7941 and [F]FE@SNAP, there is strong evidence that both radiotracers may serve as highly suitable agents for specific MCHR1 imaging.

In vivo evaluation of radiotracers targeting the melanin-concentrating hormone receptor 1: [C]SNAP-7941 and [F]FE@SNAP reveal specific uptake in the ventricular system.

The expression of chemokine receptor type 4 (CXCR4) was found co-localized with macrophages on the atherosclerotic vessel wall and participated in the initial emigration of leukocytes. Gallium-68 [Ga]Pentixafor has recently been introduced for the imaging of atherosclerosis by targeting CXCR4. We sought to evaluate human atherosclerotic lesions using [Ga]Pentixafor PET/MRI.

[68Ga]Pentixafor-PET/MRI for the detection of Chemokine receptor 4 expression in atherosclerotic plaques.

HEPES is a favorable buffer for Ga-complexations in radiochemical laboratories. The drawback of this buffer is its prescribed limit of 200 μg per recommended application volume in the final formulation. Currently, a TLC test according to the European Pharmacopoeia (Ph. Eur.) has to be performed for quantification, but this analysis suffers from low reliability and reproducibility and is based on a subjective, semi-quantitative visual evaluation. In this study, the TLC method according to the Ph. Eur. and two literature-known HPLC assays for HEPES quantification were evaluated. Additionally, the development of an improved TLC method was performed.

Development and evaluation of a rapid analysis for HEPES determination in Ga-radiotracers.

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
Monitoring of plexiform neurofibroma in children and adolescents with neurofibromatosis type 1 by [ F]FDG-PET imaging. Is it of value in asymptomatic patients? Pediatric blood & cancer\| PubMed ID: 28771999	2018
In vivo evaluation of radiotracers targeting the melanin-concentrating hormone receptor 1: [C]SNAP-7941 and [F]FE@SNAP reveal specific uptake in the ventricular system. Scientific reports\| PubMed ID: 28808288	2017
[68Ga]Pentixafor-PET/MRI for the detection of Chemokine receptor 4 expression in atherosclerotic plaques. European journal of nuclear medicine and molecular imaging\| PubMed ID: 28932900	2018
Development and evaluation of a rapid analysis for HEPES determination in Ga-radiotracers. EJNMMI research\| PubMed ID: 30353250	2018
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

Wolfgang Wadsak

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