The σ-1 receptor is a non-opioid transmembrane protein involved in various human pathologies including neurodegenerative diseases, inflammation, and cancer. The previously published ligand [18 F]FTC-146 is among the most promising tools for σ-1 molecular imaging by positron emission tomography (PET), with a potential for application in clinical diagnostics and research. However, the published six- or four-step synthesis of the tosyl ester precursor for its radiosynthesis is complicated and time-consuming. Herein, we present a simple one-step precursor synthesis followed by a one-step fluorine-18 labeling procedure that streamlines the preparation of [18 F]FTC-146. Instead of a tosyl-based precursor, we developed a one-step synthesis of the precursor analog AM-16 containing a chloride leaving group for the SN 2 reaction with 18 F-fluoride. 18 F-fluorination of AM-16 led to a moderate decay-corrected radiochemical yield (RCY = 7.5%) with molar activity (Am ) of 45.9 GBq/μmol. Further optimization of this procedure should enable routine radiopharmaceutical production of this promising PET tracer.
- Klíčová slova
- FTC-146, PET, [18F]FTC-146, chloride leaving group, fluorine-18, non-activated, precursor, radiopharmaceutical, radiosynthesis, σ-1 receptor,
- MeSH
- azepiny MeSH
- benzothiazoly MeSH
- lidé MeSH
- pozitronová emisní tomografie * metody MeSH
- radiofarmaka MeSH
- radioizotopy fluoru chemie MeSH
- receptor sigma-1 * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- 6-(3-fluoropropyl)-3-(2-(azepan-1-yl)ethyl)benzo(d)thiazol-2(3H)-one MeSH Prohlížeč
- azepiny MeSH
- benzothiazoly MeSH
- radiofarmaka MeSH
- radioizotopy fluoru MeSH
- receptor sigma-1 * MeSH
Pre-mRNA splicing is a highly coordinated process. While its dysregulation has been linked to neurological deficits, our understanding of the underlying molecular and cellular mechanisms remains limited. We implicated pathogenic variants in U2AF2 and PRPF19, encoding spliceosome subunits in neurodevelopmental disorders (NDDs), by identifying 46 unrelated individuals with 23 de novo U2AF2 missense variants (including 7 recurrent variants in 30 individuals) and 6 individuals with de novo PRPF19 variants. Eight U2AF2 variants dysregulated splicing of a model substrate. Neuritogenesis was reduced in human neurons differentiated from human pluripotent stem cells carrying two U2AF2 hyper-recurrent variants. Neural loss of function (LoF) of the Drosophila orthologs U2af50 and Prp19 led to lethality, abnormal mushroom body (MB) patterning, and social deficits, which were differentially rescued by wild-type and mutant U2AF2 or PRPF19. Transcriptome profiling revealed splicing substrates or effectors (including Rbfox1, a third splicing factor), which rescued MB defects in U2af50-deficient flies. Upon reanalysis of negative clinical exomes followed by data sharing, we further identified 6 patients with NDD who carried RBFOX1 missense variants which, by in vitro testing, showed LoF. Our study implicates 3 splicing factors as NDD-causative genes and establishes a genetic network with hierarchy underlying human brain development and function.
- Klíčová slova
- Development, Genetic diseases, Genetics, Neurodevelopment, iPS cells,
- MeSH
- enzymy opravy DNA genetika MeSH
- genové regulační sítě MeSH
- jaderné proteiny genetika MeSH
- lidé MeSH
- missense mutace MeSH
- neurovývojové poruchy * genetika MeSH
- sestřih RNA MeSH
- sestřihové faktory genetika MeSH
- spliceozomy * genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- enzymy opravy DNA MeSH
- jaderné proteiny MeSH
- PRPF19 protein, human MeSH Prohlížeč
- sestřihové faktory MeSH
PURPOSE: To derive a Delphi method-based consensus for the surgical management of Full Thickness Macular Hole (FTMH) and Lamellar Macular Hole (LMH). METHODS: 37 expert VR surgeons from 21 mainly European countries participated in Delphi method-based questionnaire for diagnosis and treatment of FTMHs and LMHs. RESULTS: A total of 36 items were rated in round 1 by 37 participants, of which 10 items achieved consensus: intraoperative verification of PVD; clinical superiority of OCT-based FTMH classification; practical ineffectiveness of ocriplasmin; circular 360° ILM peeling for small macular holes; use of regular surgical technique for the size of the hole in concomitant retinal detachment; performing complete vitrectomy; SF6 gas as preferred tamponade; cataract surgery if crystalline lens is mildly/moderately opaque; removal of both ILM and LHEP in LMH surgery. In round 2, 18 items with moderate consensus (45-70% agreement) in round 1 were rated by 35 participants. Final consensus was reached in 35% of questions related to both diagnosis and surgical procedures. CONCLUSIONS: This Delphi study provides valuable information about the consensus/disagreement on different scenarios encountered during FTMH and LMH management as a guide tosurgical decision-making. High rate of disagreement and/or variable approaches still exist for treating such relatively common conditions.
- Klíčová slova
- DELPHI consensus statement, Full thickness macular hole (FTMH), Lamellar Macular Hole (LMH), surgical decision-making, surgical management,
- Publikační typ
- časopisecké články MeSH
