Absorbed radiation dosimetry of the D3-specific PET radioligand [18F]FluorTriopride estimated using rodent and nonhuman primate

[(18)F]FluorTriopride ([(18)F]FTP) is a dopamine D(3)-receptor preferring radioligand with potential for investigation of neuropsychiatric disorders including Parkinson disease, dystonia and schizophrenia. Here we estimate human radiation dosimetry for [(18)F]FTP based on the ex-vivo biodistribution in rodents and in vivo distribution in nonhuman primates. Biodistribution data were generated using male and female Sprague-Dawley rats injected with ~370 KBq of [(18)F]FTP and euthanized at 5, 30, 60, 120, and 240 min. Organs of interest were dissected, weighed and assayed for radioactivity content. PET imaging studies were performed in two male and one female macaque fascicularis administered 143-190 MBq of [(18)F]FTP and scanned whole-body in sequential sections. Organ residence times were calculated based on organ time activity curves (TAC) created from regions of Interest. OLINDA/EXM 1.1 was used to estimate human radiation dosimetry based on scaled organ residence times. In the rodent, the highest absorbed radiation dose was the upper large intestines (0.32-0.49 mGy/MBq), with an effective dose of 0.07 mSv/MBq in males and 0.1 mSv/MBq in females. For the nonhuman primate, however, the gallbladder wall was the critical organ (1.81 mGy/MBq), and the effective dose was 0.02 mSv/MBq. The species discrepancy in dosimetry estimates for [(18)F]FTP based on rat and primate data can be attributed to the slower transit of tracer through the hepatobiliary track of the primate compared to the rat, which lacks a gallbladder. Out findings demonstrate that the nonhuman primate model is more appropriate model for estimating human absorbed radiation dosimetry when hepatobiliary excretion plays a major role in radiotracer elimination

Butanethiol adsorption and dissociation on Ag (111): A periodic DFT study

International audienceThe molecular and dissociative adsorption of butanethiol (C4H9SH) on regular Ag (111) surfaces has been studied by means of periodic ab initio density functional techniques. In molecular form, butanethiol is bound to the surface only by weak polarization-induced forces with the C–S axis tilted by 38° relative to the normal surface. The S atom occupies a position between a hollow fcc and a bridge site. In the dissociative adsorption process, the S–H bond breaks leading to butanethiolate. The S atom of the thiolate also occupies a threefold position, slightly displaced to a hollow fcc site compared to the thiol adsorption case. The C–S axis of the thiolate is tilted by about 37°. The calculated adsorption energies show that the butanethiol and butanethiolate have similar adsorption ability. The computed reaction pathway for the S–H dissociation gives an activation energy of 0.98 eV indicating that the thiolate formation from thiol, although not spontaneous at room temperature, might be feasible on silver surfaces. The dissociation process induces both adsorbate and surface polarization with a significant charge transfer from the substrate to the adsorbate

Using the structural diversity of RNA: protein interfaces to selectively target RNA with small molecules in cells: methods and perspectives

International audienceIn recent years, RNA has gained traction both as a therapeutic molecule and as a therapeutic target in several human pathologies. In this review, we consider the approach of targeting RNA using small molecules for both research and therapeutic purposes. Given the primary challenge presented by the low structural diversity of RNA, we discuss the potential for targeting RNA: protein interactions to enhance the structural and sequence specificity of drug candidates. We review available tools and inherent challenges in this approach, ranging from adapted bioinformatics tools to in vitro and cellular high-throughput screening and functional analysis. We further consider two critical steps in targeting RNA/protein interactions: first, the integration of in silico and structural analyses to improve the efficacy of molecules by identifying scaffolds with high affinity, and second, increasing the likelihood of identifying on-target compounds in cells through a combination of high-throughput approaches and functional assays. We anticipate that the development of a new class of molecules targeting RNA: protein interactions to prevent physio-pathological mechanisms could significantly expand the arsenal of effective therapeutic compounds

Synthesis, Radiolabeling, and Biological Evaluation of (<i>R</i>)- and (<i>S</i>)‑2-Amino-5‑[¹⁸F]fluoro-2-methylpentanoic Acid ((<i>R</i>)‑, (<i>S</i>)‑[¹⁸F]FAMPe) as Potential Positron Emission Tomography Tracers for Brain Tumors

A novel ¹⁸F-labeled α,α-disubstituted amino acid-based tracer, 2-amino-5-[¹⁸F]­fluoro-2-methylpentanoic acid ([¹⁸F]­FAMPe), has been developed for brain tumor imaging with a longer alkyl side chain than previously reported compounds to increase brain availability via system L amino acid transport. Both enantiomers of [¹⁸F]­FAMPe were obtained in good radiochemical yield (24–52% <i>n</i> = 8) and high radiochemical purity (>99%). In vitro uptake assays in mouse DBT gliomas cells revealed that (<i>S</i>)-[¹⁸F]­FAMPe enters cells partly via sodium-independent system L transporters and also via other nonsystem A transport systems including transporters that recognize glutamine. Biodistribution and small animal PET/CT studies in the mouse DBT model of glioblastoma showed that both (<i>R</i>)- and (<i>S</i>)-[¹⁸F]­FAMPe have good tumor imaging properties with the (<i>S</i>)-enantiomer providing higher tumor uptake and tumor to brain ratios. Comparison of the SUVs showed that (<i>S</i>)-[¹⁸F]­FAMPe had higher tumor to brain ratios compared to (<i>S</i>)-[¹⁸F]­FET, a well-established system L substrate

Synthesis and Biological Evaluation of (<i>S</i>)‑Amino-2-methyl-4‑[⁷⁶Br]bromo-3‑(<i>E</i>)‑butenoic Acid (BrVAIB) for Brain Tumor Imaging

The novel compound, (<i>S</i>)-amino-2-methyl-4-[⁷⁶Br]­bromo-3-(<i>E</i>)-butenoic acid (BrVAIB, [⁷⁶Br]<b>5</b>), was characterized against the known system A tracer, IVAIB ([¹²³I]<b>8</b>). [⁷⁶Br]<b>5</b> was prepared in a 51% ± 19% radiochemical yield with high radiochemical purity (≥98%). The biological properties of [⁷⁶Br]<b>5</b> were compared with those of [¹²³I]<b>8</b>. Results showed that [⁷⁶Br]<b>5</b> undergoes mixed amino acid transport by system A and system L transport, while [¹²³I]<b>8</b> had less uptake by system L. [⁷⁶Br]<b>5</b> demonstrated higher uptake than [¹²³I]<b>8</b> in DBT tumors 1 h after injection (3.7 ± 0.4% ID/g vs 1.5 ± 0.3% ID/g) and also showed higher uptake vs [¹²³I]<b>8</b> in normal brain. Small animal PET studies with [⁷⁶Br]<b>5</b> demonstrated good tumor visualization of intracranial DBTs up to 24 h with clearance from normal tissues. These results indicate that [⁷⁶Br]<b>5</b> is a promising PET tracer for brain tumor imaging and lead compound for a mixed system A and system L transport substrate

Effect of α-Methyl versus α-Hydrogen Substitution on Brain Availability and Tumor Imaging Properties of Heptanoic [F-18]Fluoroalkyl Amino Acids for Positron Emission Tomography (PET).

International audienceTwo [(18)F]fluoroalkyl substituted amino acids differing only by the presence or absence of a methyl group on the α-carbon, (S)-2-amino-7-[(18)F]fluoro-2-methylheptanoic acid ((S)-[(18)F]FAMHep, (S)-[(18)F]14) and (S)-2-amino-7-[(18)F]fluoroheptanoic acid ((S)-[(18)F]FAHep, (S)-[(18)F]15), were developed for brain tumor imaging and compared to the well-established system L amino acid tracer, O-(2-[(18)F]fluoroethyl)-l-tyrosine ([(18)F]FET), in the delayed brain tumor (DBT) mouse model of high-grade glioma. Cell uptake, biodistribution, and PET/CT imaging studies showed differences in amino acid transport of these tracer by DBT cells. Recognition of (S)-[(18)F]15 but not (S)-[(18)F]14 by system L amino acid transporters led to approximately 8-10-fold higher uptake of the α-hydrogen substituted analogue (S)-[(18)F]15 in normal brain. (S)-[(18)F]15 had imaging properties similar to those of (S)-[(18)F]FET in the DBT tumor model while (S)-[(18)F]14 afforded higher tumor to brain ratios due to much lower uptake by normal brain. These results have important implications for the future development of α-alkyl and α,α-dialkyl substituted amino acids for brain tumor imaging

A molecular insight of Hes5-dependent inhibition of myelin gene expression: old partners and new players

This study identifies novel mechanisms of Hes5 function in developmental myelination. We report here upregulation of myelin gene expression in Hes5−/− mice compared to wild-type siblings and downregulation in overexpressing progenitors. This effect was only partially explained by the ability to regulate the levels of Mash1 and bind to N boxes in myelin promoters, as deletion of the DNA-binding domain of Hes5 did not suppress its inhibitory role on myelin gene expression. Novel mechanisms of Hes5 function in the oligodendrocyte lineage include the regulation of feedback loops with the cell-specific transcriptional activator Sox10. In progenitors with low levels of Sox10, Hes5 further decreases the bioavailability of this protein by transcriptional inhibition and direct sequestration of this activator. Increasing levels of Sox10 in progenitors, in turn, bind to Hes5 and titrate out its inhibitory effect by sequestration and displacement of the repressive complexes from myelin promoters. Thus, Hes5-dependent modulation of myelin gene expression involves old players (i.e. Mash1) and novel mechanisms of transcriptional regulation that include cell-specific regulatory loops with transcriptional activators (i.e. Sox10)