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

The decision whether an in-house produced short-lived radiopharmaceutical can be applied in-vivo is based on (1) the fulfilment of all quality criteria; (2) the availability of enough radioactivity for subsequent imaging; and (3) a molar activity (MA) above the set limits to guarantee safe administration without competing occupancy of the non-radioactive compound; and (4) an activity concentration, which is high enough for the application in certain preclinical studies. Hence, time reduction can be of major importance to increase final product yields, MA and activity concentrations. Usually, optimization in this respect only focuses on the radiotracer preparation steps but especially quality control (QC) is rarely even mentioned. Therefore, aim of this work is the establishment of optimized conditions for chromatographic analysis using HPLC within the QC to enable a significant time reduction, which then directly leads to an increase in available amount of radioactive product as well as MA at the time of application.

Speed matters to raise molar radioactivity: Fast HPLC shortens the quality control of C-11 PET-tracers.

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.

Alterations of the 5-HT receptor and BDNF have consistently been associated with affective disorders. Two functional single nucleotide polymorphisms (SNPs), rs6295 of the serotonin 1A receptor gene (HTR1A) and rs6265 of brain-derived neurotrophic factor gene (BDNF), may impact transcriptional regulation and expression of the 5-HT receptor. Here we investigated interaction effects of rs6295 and rs6265 on 5-HT receptor binding. Forty-six healthy subjects were scanned with PET using the radioligand [carbonyl-C]WAY-100635. Genotyping was performed for rs6265 and rs6295. Subjects showing a genotype with at least three risk alleles (G of rs6295 or A of rs6265) were compared to control genotypes. Cortical surface binding potential (BP) was computed for 32 cortical regions of interest (ROI). Mixed model was applied to study main and interaction effects of ROI and genotype. ANOVA was used for post hoc analyses. Individuals with the risk genotypes exhibited an increase in 5-HT receptor binding by an average of 17% (mean BP 3.56 ± 0.74 vs. 2.96 ± 0.88). Mixed model produced an interaction effect of ROI and genotype on BP and differences could be demonstrated in 10 ROI post hoc. The combination of disadvantageous allelic expression of rs6295 and rs6265 may result in a 5-HT receptor profile comparable to affective disorders as increased 5-HT receptor binding is a well published phenotype of depression. Thus, epistasis between BDNF and HTR1A may contribute to the multifactorial risk for affective disorders and our results strongly advocate further research on this genetic signature in affective disorders.

Article	Year
Speed matters to raise molar radioactivity: Fast HPLC shortens the quality control of C-11 PET-tracers. Nuclear medicine and biology\| PubMed ID: 29227813	2018
Optimization of the Automated Synthesis of [11C]mHED-Administered and Apparent Molar Activities. Pharmaceuticals (Basel, Switzerland)\| PubMed ID: 30646635	2019
Epistasis of HTR1A and BDNF risk genes alters cortical 5-HT1A receptor binding: PET results link genotype to molecular phenotype in depression. Translational psychiatry\| PubMed ID: 30664620	2019

Cecile Philippe

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