Showing papers by "Szabolcs Lehel published in 2020"
TL;DR: It is confirmed that psilocybin intake is associated with long-term increases in Openness and - as a novel finding - mindfulness, which may be a key element of p silocybin therapy.
68 citations
TL;DR: Good correlation between in vivo measured SUV ratios and in vitro measures of HDAC 1–3 proteins is found, supporting that [11C]Martinostat provides a good in vivo measure of the cerebral HDAC1–3 protein levels.
Abstract: With the emerging knowledge about the impact of epigenetic alterations on behavior and brain disorders, the ability to measure epigenetic alterations in brain tissue in vivo has become critically important We present the first in vivo/in vitro cross-validation of the novel positron emission tomography (PET) radioligand [11C]Martinostat in the pig brain with regard to its ability to measure histone deacetylase 1–3 (HDAC1–3) levels in vivo Nine female Danish landrace pigs underwent 121-min dynamic PET scans with [11C]Martinostat We quantified [11C]Martinostat uptake using both a simple ratio method and kinetic models with arterial input function By the end of the scan, the animals were euthanized and the brains were extracted We measured HDAC1–3 protein levels in frontal cortex, cerebellum vermis, and hippocampus and compared the protein levels and regional outcome values to the [11C]Martinostat PET quantification [11C]Martinostat distributed widely across brain regions, with the highest uptake in the cerebellum vermis and the lowest in the olfactory bulbs Based on the Akaike information criterion, the quantification was most reliably performed by Ichise MA1 kinetic modeling, but since the radioligand displayed very slow kinetics, we also calculated standard uptake value (SUV) ratios which correlated well with VT The western blots revealed higher brain tissue protein levels of HDAC1/2 compared to HDAC3, and HDAC1 and HDAC2 levels were highly correlated in all three investigated brain regions The in vivo SUV ratio measure correlated well with the in vitro HDAC1–3 levels, whereas no correlation was found between VT values and HDAC levels We found good correlation between in vivo measured SUV ratios and in vitro measures of HDAC 1–3 proteins, supporting that [11C]Martinostat provides a good in vivo measure of the cerebral HDAC1–3 protein levels
7 citations
TL;DR: Results indicate that selective 5-HT7 receptor imaging might be possible when more selective non-P-gp substrates are identified, and suggest exploration of this structural class is suggested.
Abstract: The serotonin 7 (5-HT7 ) receptor is suggested to be involved in a broad variety of CNS disorders, but very few in vivo tools exist to study this important target. Molecular imaging with positron emission tomography (PET) would enable an in vivo characterization of the 5-HT7 receptor. However, no clinical PET radiotracer exists for this receptor, and thus we aimed to develop such a tracer. In this study, we present the preclinical evaluation of [11 C]Cimbi-701. Cimbi-701 was synthesized in a one-step procedure starting from SB-269970. Its selectivity profile was determined using an academic screening platform (NIMH Psychoactive Drug Screening Program). Successful radiolabeling of [11 C]Cimbi-701 and subsequent in vivo evaluation was conducted in rats, pigs and baboon. In vivo specificity was investigated by 5-HT7 and σ receptor blocking studies. P-gp efflux transporter dependency was investigated using elacridar. [11 C]Cimbi-701 could successfully be synthesized. Selectivity profiling revealed high affinity for the 5-HT7 (Ki = 18 nM), σ-1 (Ki = 9.2 nM) and σ-2 (Ki = 1.6 nM) receptors. In rats, [11 C]Cimbi-701 acted as a strong P-gp substrate. After P-gp inhibition, rat brain uptake could specifically be blocked by 5-HT7 and σ receptor ligands. In pig, high brain uptake and specific 5-HT7 and σ-receptor binding was found for [11 C]Cimbi-701 without P-gp inhibition. Finally, low brain uptake was found in baboons. Both the specific σ-receptor binding and the low brain uptake of [11 C]Cimbi-701 displayed in baboon discouraged further translation to humans. Instead, we suggest exploration of this structural class as results indicate that selective 5-HT7 receptor imaging might be possible when more selective non-P-gp substrates are identified.
4 citations
TL;DR: Six 18F-labeled (arylpiperazinyl-butyl)oxindole derivatives were synthesized and were radiolabeled in sufficient radiochemical yields, purities and molar activities for future in vivo evaluation in rodents.
Abstract: In this work, a fragment-based labeling procedure was developed based on condensation reactions. Six 18F-labeled (arylpiperazinyl-butyl)oxindole derivatives were synthesized. These structures are interesting lead compounds with respect to development of a 5-HT7R PET tracer. They were radiolabeled in sufficient radiochemical yields, purities and molar activities for future in vivo evaluation in rodents.
1 citations