Synthesis and Characterization of a “Clickable” PBR28 TSPO-Selective Ligand Derivative Suitable for the Functionalization of Biodegradable Polymer Nanoparticles
Open Access
- 28 June 2021
- journal article
- research article
- Published by MDPI AG in Nanomaterials
- Vol. 11 (7), 1693
- https://doi.org/10.3390/nano11071693
Abstract
Reactive microgliosis is a pathological hallmark that accompanies neuronal demise in many neurodegenerative diseases, ranging from acute brain/spinal cord injuries to chronic diseases, such as amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD) and age-related dementia. One strategy to assess and monitor microgliosis is to use positron emission tomography (PET) by exploiting radioligands selective for the 18 kDa translocator protein (TSPO) which is highly upregulated in the brain in pathological conditions. Several TSPO ligands have been developed and validated, so far. Among these, PBR28 has been widely adopted for PET imaging at both preclinical and clinical levels, thanks to its high brain penetration and high selectivity. For this reason, PBR28 represents a good candidate for functionalization strategies, where this ligand could be exploited to drive selective targeting of TSPO-expressing cells. Since the PBR28 structure lacks functional moieties that could be exploited for derivatization, in this work we explored a synthetic pathway for the synthesis of a PBR28 derivative carrying an alkyne group (PBR-alkyne), enabling the fast conjugation of the ligand through azide-alkyne cycloaddition, also known as click-chemistry. As a proof of concept, we demonstrated in silico that the derivatized PBR28 ligand maintains the capability to fit into the TSPO binding pocked, and we successfully exploited PBR-alkyne to decorate zwitterionic biodegradable polymer nanoparticles (NPs) resulting in efficient internalization in cultured microglia-like cell lines.Funding Information
- Amyotrophic Lateral Sclerosis Association (20-IIP-525)
- U.S. Department of Defense (W81XWH-17-1-0036)
- University and Research (MIUR): Dipartimenti di Eccellenza Program (Dept. of Biology and Biotechnology “L. Spallanzani”, University of Pavia)
This publication has 30 references indexed in Scilit:
- Translocator Protein (TSPO) as a Potential Biomarker in Human CancersInternational Journal of Molecular Sciences, 2018
- Influence of alcoholism and cholesterol on TSPO binding in brain: PET [11C]PBR28 studies in humans and rodentsNeuropsychopharmacology, 2018
- Bridging Pharmaceutical Chemistry with Drug and Nanoparticle Targeting to Investigate the Role of the 18-kDa Translocator Protein TSPOChemMedChem, 2017
- Recent Progress in the Development of TSPO PET Ligands for Neuroinflammation Imaging in Neurological DiseasesNuclear Medicine and Molecular Imaging, 2017
- A comprehensive review of amyotrophic lateral sclerosisSurgical Neurology International, 2015
- A self-internalizing mitochondrial TSPO targeting imaging probe for fluorescence, MRI and EMRSC Advances, 2014
- Reactive Astrocytes Overexpress TSPO and Are Detected by TSPO Positron Emission Tomography ImagingJournal of Neuroscience, 2012
- An 18-kDa Translocator Protein (TSPO) Polymorphism Explains Differences in Binding Affinity of the PET Radioligand PBR28Journal of Cerebral Blood Flow & Metabolism, 2011
- Synthesis and Evaluation in Monkey of Two Sensitive 11C-Labeled Aryloxyanilide Ligands for Imaging Brain Peripheral Benzodiazepine Receptors In VivoJournal of Medicinal Chemistry, 2007
- Peripheral benzodiazepine receptors and mitochondrial functionNeurochemistry International, 2002