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Synthesis and Characterization of a "Clickable" PBR28 TSPO-Selective Ligand Derivative Suitable for the Functionalization of Biodegradable Polymer Nanoparticles.

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.

SUBMITTER: Auriemma R

PROVIDER: S-EPMC8308144 | biostudies-literature |

REPOSITORIES: biostudies-literature

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"Clickable" polymer nanoparticles: a modular scaffold for surface functionalization.

Project description:The versatility of copper-catalyzed alkyne-azide coupling (CuAAC) in functionalizing drug-loaded polymer nanoparticles is demonstrated via the modification of surfaces of acetylene-functionalized PNPs with folate, biotin, and gold nanoparticles.

| S-EPMC3861897 | biostudies-other

Influence of TSPO genotype on 11C-PBR28 standardized uptake values.

Project description:UNLABELLED:(11)C-PBR28 binds to the high-affinity state of the translocator protein 18 kDa (TSPO). A single-nucleotide polymorphism (rs6971) within the human TSPO gene determines the affinity state of the TSPO. The rs6971 genotype determines whether individuals express the high-, low-, or mixed-affinity phenotype of TSPO. The rs6971 genotype corresponds to in vivo (11)C-PBR28 binding, as measured quantitatively by total volume of distribution. However, it is not known whether standardized uptake value (SUV) can detect differences in brain (11)C-PBR28 uptake by TSPO genotype. METHODS:Thirty-two older adults (71.8 ± 7.94 y old) underwent (11)C-PBR28 PET scanning; rs6971 genotype was imputed after genomewide genotyping. SUV was extracted for several brain regions. The sample included 19 C/C carriers (high-affinity phenotype), 12 T/C carriers (mixed-affinity), and 1 T/T carrier (low-affinity) for rs6971. RESULTS:SUV was 30% lower in T/C subjects than in C/C subjects. CONCLUSION:The results indicate that brain (11)C-PBR28 SUV is sensitive to TSPO genotype.

| S-EPMC3740346 | biostudies-literature

"Clickable" Polymer Brush Interfaces: Tailoring Monovalent to Multivalent Ligand Display for Protein Immobilization and Sensing.

Project description:Facile and effective functionalization of the interface of polymer-coated surfaces allows one to dictate the interaction of the underlying material with the chemical and biological analytes in its environment. Herein, we outline a modular approach that would enable installing a variety of "clickable" handles onto the surface of polymer brushes, enabling facile conjugation of various ligands to obtain functional interfaces. To this end, hydrophilic anti-biofouling poly(ethylene glycol)-based polymer brushes are fabricated on glass-like silicon oxide surfaces using reversible addition-fragmentation chain transfer (RAFT) polymerization. The dithioester group at the chain-end of the polymer brushes enabled the installation of azide, maleimide, and terminal alkene functional groups, using a post-polymerization radical exchange reaction with appropriately functionalized azo-containing molecules. Thus, modified polymer brushes underwent facile conjugation of alkyne or thiol-containing dyes and ligands using alkyne-azide cycloaddition, Michael addition, and radical thiol-ene conjugation, respectively. Moreover, we demonstrate that the radical exchange approach also enables the installation of multivalent motifs using dendritic azo-containing molecules. Terminal alkene groups containing dendrons amenable to functionalization with thiol-containing molecules using the radical thiol-ene reaction were installed at the interface and subsequently functionalized with mannose ligands to enable sensing of the Concanavalin A lectin.

| S-EPMC9501913 | biostudies-literature

Chemical synthesis and functionalization of clickable glycosylphosphatidylinositol anchors.

Project description:Glycosylphosphatidylinositol (GPI) anchorage is a common posttranslational modification of eukaryotic proteins. Chemical synthesis of structurally defined GPIs and GPI derivatives is a necessary step toward understanding the properties and functions of these molecules in biological systems. In this work, the synthesis of several functionalized GPI anchors was accomplished using the para-methoxybenzyl (PMB) group for permanent hydroxyl protection, which allowed the incorporation of functionalities that are incompatible with permanent protecting groups traditionally used in carbohydrate synthesis. A flexible convergent-divergent assembly strategy enabled efficient access to a diverse set of target structures, including "clickable" Alkynyl-GPIs 1 and 2 and Azido-GPI 3. For global deprotection, a one-pot reaction was employed to afford the target GPIs in excellent yields (85-97%). Fully deprotected clickable GPIs 2 and 3 were readily conjugated to imaging and affinity probes via Cu(I)-catalyzed and Cu-free strain-promoted [3+2] cycloaddition, respectively, resulting in GPI-Fluor 4 and GPI-Biotin 5.

| S-EPMC3233219 | biostudies-literature

Orthogonally "Clickable" Biodegradable Nanofibers: Tailoring Biomaterials for Specific Protein Immobilization.

Project description:Multifunctionalizable polymeric nanofibers can be tailored for various biomedical applications by selective conjugation of small molecules and bioactive ligands. This study reports the design, synthesis, and application of novel biodegradable polyester-based nanofibers bearing metal-free "clickable" handles. Polylactide-based polymers were synthesized using organo-catalyzed ring-opening polymerization to contain "clickable" chain-end functional groups that specifically react through radical or nucleophilic thiol-ene reactions. A furan-protected maleimide-containing hydroxyl-bearing initiator yielded polymers containing strained oxanorbornene unit at their chain end. In addition, postpolymerization thermal treatment provides maleimide end group-containing polymers. Solution electrospinning method was utilized to obtain bead-free nanofibers. Efficient conjugation on these nanofibers was demonstrated using metal-free conjugation reactions. It was observed that polylactide nanofibers undergo extensive biofouling, which limits their possible utilization for specific biomolecular immobilization. To alleviate this problem, polymers were modified to contain two orthogonally reactive functional groups, namely, the oxanorbornene unit and an azide group at their chain ends. The former reactive handle was used for conjugation of poly(ethylene glycol) chains to impart hydrophilicity and thus an antibiofouling ability, whereas the azide group undergoes strain-promoted azide-alkyne cycloaddition to install a protein-binding ligand such as biotin. These nanofibers were able to specifically immobilize the protein streptavidin with minimal nonspecific adsorption.

| S-EPMC6648765 | biostudies-literature

Synthesis, Characterization, and in Vitro Evaluation of a New TSPO-Selective Bifunctional Chelate Ligand.

Project description:The 18-kDa translocator protein (TSPO) is overexpressed in many types of cancers and is also abundant in activated microglial cells occurring in inflammatory neurodegenerative diseases. Thus, TSPO has become an extremely attractive subcellular target not only for imaging disease states overexpressing this protein, but also for a selective mitochondrial drug delivery. In this work we report the synthesis, the characterization, and the in vitro evaluation of a new TSPO-selective ligand, 2-(8-(2-(bis(pyridin-2-yl)methyl)amino)acetamido)-2-(4-chlorophenyl)H-imidazo[1,2-a]pyridin-3-yl)-N,N-dipropylacetamide (CB256), which fulfils the requirements for a bifunctional chelate approach. The goal was to provide a new TSPO ligand that could be used further to prepare coordination complexes of a metallo drug to be used in diagnosis and therapy. However, the ligand itself proved to be a potent tumor cell growth inhibitor and DNA double-strand breaker.

| S-EPMC4060941 | biostudies-literature

Data in support of preparation and functionalization of a clickable polycarbonate monolith.

Project description:This data article provides supplementary figures to the research article entitled, "Phase separation approach to a reactive polycarbonate monolith for "click" modifications" (Xin et al., Polymer, 2015, doi:10.1016/j.polymer.2015.04.008). Here, the nitrogen adsorption/desorption isotherms of the prepared porous polycarbonate monolith are shown to classify its inner structure and calculate the specific surface area. The monoliths were modified by using the thiol-ene click chemistry and the olefin metathesis, which was examined by contact angle measurements, FT-IR, solid state 13C NMR spectroscopy as well as thermogravimetric analysis.

| S-EPMC5063809 | biostudies-other

Clickable Polymer Ligand-Functionalized Iron Oxide Nanocubes: A Promising Nanoplatform for 'Local Hot Spots' Magnetically Triggered Drug Release.

Project description:Exploiting the local heat on the surface of magnetic nanoparticles (MNPs) upon exposure to an alternating magnetic field (AMF) to cleave thermal labile bonds represents an interesting approach in the context of remotely triggered drug delivery. Here, taking advantages of a simple and scalable two-step ligand exchange reaction, we have prepared iron oxide nanocubes (IONCs) functionalized with a novel multifunctional polymer ligand having multiple catechol moieties, furfuryl pendants, and polyethylene glycol (PEG) side chains. Catechol groups ensure a strong binding of the polymer ligands to the IONCs surface, while the PEG chains provide good colloidal stability to the polymer-coated IONCs. More importantly, furfuryl pendants on the polymer enable to click the molecules of interest (either maleimide-fluorescein or maleimide-doxorubicin) via a thermal labile Diels-Alder adduct. The resulting IONCs functionalized with a fluorescein/doxorubicin-conjugated polymer ligand exhibit good colloidal stability in buffer saline and serum solution along with outstanding heating performance in aqueous solution or even in viscous media (81% glycerol/water) when exposed to the AMF of clinical use. The release of conjugated bioactive molecules such as fluorescein and doxorubicin could be boosted by applying AMF conditions of clinical use (16 kAm-1 and 110 kHz). It is remarkable that the magnetic hyperthermia-mediated release of the dye/drug falls in the concentration range 1.0-5.0 μM at an IONCs dose as low as 0.5 gFe/L and at no macroscopical temperature change. This local release effect makes this magnetic nanoplatform a potential tool for drug delivery with remote magnetic hyperthermia actuation and with a dose-independent action of MNPs.

| S-EPMC9634696 | biostudies-literature

Determination of [(11)C]PBR28 binding potential in vivo: a first human TSPO blocking study.

Project description:Positron emission tomography (PET) targeting the 18?kDa translocator protein (TSPO) is used to quantify neuroinflammation. Translocator protein is expressed throughout the brain, and therefore a classical reference region approach cannot be used to estimate binding potential (BPND). Here, we used blockade of the TSPO radioligand [(11)C]PBR28 with the TSPO ligand XBD173, to determine the non-displaceable volume of distribution (VND), and hence estimate the BPND. A total of 26 healthy volunteers, 16 high-affinity binders (HABs) and 10 mixed affinity binders (MABs) underwent a [(11)C]PBR28 PET scan with arterial sampling. Six of the HABs received oral XBD173 (10 to 90?mg), 2?hours before a repeat scan. In XBD173-dosed subjects, VND was estimated via the occupancy plot. Values of BPND for all subjects were calculated using this VND estimate. Total volume of distribution (VT) of MABs (2.94±0.31) was lower than VT of HABs (4.33±0.29) (P<0.005). There was dose-dependent occupancy of TSPO by XBD173 (ED50=0.34±0.13?mg/kg). The occupancy plot provided a VND estimate of 1.98 (1.69, 2.26). Based on these VND estimates, BPND for HABs is approximately twice that of MABs, consistent with predictions from in vitro data. Our estimates of [(11)C]PBR28 VND and hence BPND in the healthy human brain are consistent with in vitro predictions. XBD173 blockade provides a practical means of estimating VND for TSPO targeting radioligands.

| S-EPMC4050243 | biostudies-literature

Site Selective Chlorination of C(sp<sup>3</sup> )-H Bonds Suitable for Late-Stage Functionalization.

Project description:C(sp3 )-Cl bonds are present in numerous biologically active small molecules, and an ideal route for their preparation is by the chlorination of a C(sp3 )-H bond. However, most current methods for the chlorination of C(sp3 )-H bonds are insufficiently site selective and tolerant of functional groups to be applicable to the late-stage functionalization of complex molecules. We report a method for the highly selective chlorination of tertiary and benzylic C(sp3 )-H bonds to produce the corresponding chlorides, generally in high yields. The reaction occurs with a mixture of an azidoiodinane, which generates a selective H-atom abstractor under mild conditions, and a readily-accessible and inexpensive copper(II) chloride complex, which efficiently transfers a chlorine atom. The reaction's exceptional functional group tolerance is demonstrated by the chlorination of >30 diversely functionalized substrates and the late-stage chlorination of a dozen derivatives of natural products and active pharmaceutical ingredients.

| S-EPMC8594412 | biostudies-literature

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