EJNMMI Radiopharm Chem
October 2024
Modified messenger RNA (mRNA) represents a rapidly emerging class of therapeutic drug product. Development of robust stability indicating methods for control of product quality are therefore critical to support successful pharmaceutical development. This paper presents an ion-pair reversed-phase liquid chromatography (IP-RPLC) method to characterise modified mRNA exposed to a wide set of stress-inducing conditions, relevant for pharmaceutical development of an mRNA drug product.
View Article and Find Full Text PDFBackground: The brain is a challenging target for antibody-based positron emission tomography (immunoPET) imaging due to the restricted access of antibody-based ligands through the blood-brain barrier (BBB). To overcome this physiological obstacle, we have previously developed bispecific antibody ligands that pass through the BBB via receptor-mediated transcytosis. While these radiolabelled ligands have high affinity and specificity, their long residence time in the blood and brain, typical for large molecules, poses another challenge for PET imaging.
View Article and Find Full Text PDFDeposition of amyloid beta (Aβ) into plaques is a major hallmark of Alzheimer's disease (AD). Different amyloid precursor protein (APP) mutations cause early-onset AD by altering the production or aggregation properties of Aβ. We recently identified the Uppsala APP mutation (APPUpp), which causes Aβ pathology by a triple mechanism: increased β-secretase and altered α-secretase APP cleavage, leading to increased formation of a unique Aβ conformer that rapidly aggregates and deposits in the brain.
View Article and Find Full Text PDFBackground: Beta-cell replacement methods such as transplantation of isolated donor islets have been proposed as a curative treatment of type 1 diabetes, but widespread application is challenging due to shortages of donor tissue and the need for continuous immunosuppressive treatments. Stem-cell-derived islets have been suggested as an alternative source of beta cells, but face transplantation protocols optimization difficulties, mainly due to a lack of available methods and markers to directly monitor grafts survival, as well as their localization and function. Molecular imaging techniques and particularly positron emission tomography has been suggested as a tool for monitoring the fate of islets after clinical transplantation.
View Article and Find Full Text PDFSynaptic alterations in certain brain structures are related to cognitive decline in neurodegeneration and in aging. Synaptic loss in many neurodegenerative diseases can be visualized by positron emission tomography (PET) imaging of synaptic vesicle glycoprotein 2A (SV2A). However, the use of SV2A PET for studying synaptic changes during aging is not particularly explored.
View Article and Find Full Text PDFThe progressive loss of beta-cell mass is a hallmark of diabetes and has been suggested as a complementary approach to studying the progression of diabetes in contrast to the beta-cell function. Non-invasive nuclear medicinal imaging techniques such as Positron Emission Tomography using radiation emitting tracers have thus been suggested as more viable methodologies to visualize and quantify the beta-cell mass with sufficient sensitivity. The transmembrane G protein-coupled receptor GPR44 has been identified as a biomarker for monitoring beta-cell mass.
View Article and Find Full Text PDFSmall molecule imaging agents such as [C]PiB, which bind to the core of insoluble amyloid-β (Aβ) fibrils, are useful tools in Alzheimer's disease (AD) research, diagnostics, and drug development. However, the [C]PiB PET signal saturates early in the disease progression and does not detect soluble or diffuse Aβ pathology which are believed to play important roles in the disease progression. Antibodies, modified into a bispecific format to enter the brain via receptor-mediated transcytosis, could be a suitable alternative because of their diversity and high specificity for their target.
View Article and Find Full Text PDFImmunotherapy targeting aggregated alpha-synuclein (αSYN) is a promising approach for the treatment of Parkinson's disease. However, brain penetration of antibodies is hampered by their large size. Here, RmAbSynO2-scFv8D3, a modified bispecific antibody that targets aggregated αSYN and binds to the transferrin receptor for facilitated brain uptake, was investigated to treat αSYN pathology in transgenic mice.
View Article and Find Full Text PDFPositron emission tomography (PET), a medical imaging technique allowing for studies of the living human brain, has gained an important role in clinical trials of novel drugs against Alzheimer's disease (AD). For example, PET data contributed to the conditional approval in 2021 of aducanumab, an antibody directed towards amyloid-beta (Aβ) aggregates, by showing a dose-dependent reduction in brain amyloid after treatment. In parallel to clinical studies, preclinical studies in animal models of Aβ pathology may also benefit from PET as a tool to detect target engagement and treatment effects of anti-Aβ drug candidates.
View Article and Find Full Text PDFBiomarkers for the measurement of islets of Langerhans could help elucidate the etiology of diabetes. Synaptic vesicle glycoprotein 2 A (SV2A) is a potential marker reported to be localized in the endocrine pancreas. [C]UCB-J is a novel positron emission tomography (PET) radiotracer that binds to SV2A and was previously evaluated as a synaptic marker in the central nervous system.
View Article and Find Full Text PDFTransition metals, such as zinc, are essential micronutrients in all organisms, but also highly toxic in excessive amounts. Heavy-metal transporting P-type (P) ATPases are crucial for homeostasis, conferring cellular detoxification and redistribution through transport of these ions across cellular membranes. No structural information is available for the P-ATPases, the subclass with the broadest cargo scope, and hence even their topology remains elusive.
View Article and Find Full Text PDFJ Labelled Comp Radiopharm
September 2021
The Suzuki-type cross coupling reaction is a palladium-mediated multistep reaction that has been used to synthesize several C-labeled tracers for PET. However, the impact of the selected organoborane reagent and reaction medium on the radiochemical yield (RCY) has not been thoroughly investigated. To bridge this gap, we studied the synthesis of 1-[ C]methylnaphthalene using four different organoborane precursors in reactions performed in DMF/water and THF/water.
View Article and Find Full Text PDFThe positron emission tomography (PET) radioligand [C]UCB-J binds to synaptic vesicle protein 2A (SV2A) and is used to investigate synaptic density in the living brain. Clinical studies have indicated reduced [C]UCB-J binding in Alzheimer's disease (AD) and Parkinson's disease (PD) brains compared to healthy controls. Still, it is unknown whether [C]UCB-J PET can visualise synaptic loss in mouse models of these disorders.
View Article and Find Full Text PDFPET imaging of amyloid-β (Aβ) has become an important component of Alzheimer disease diagnosis. C-Pittsburgh compound B (C-PiB) and analogs bind to fibrillar Aβ. However, levels of nonfibrillar, soluble, aggregates of Aβ appear more dynamic during disease progression and more affected by Aβ-reducing treatments.
View Article and Find Full Text PDFA validated imaging marker for beta-cell mass would improve understanding of diabetes etiology and enable new strategies in therapy development. We previously identified the membrane-spanning protein GPR44 as highly expressed and specific to the beta cells of the pancreas. The selective GPR44 antagonist MK-7246 was radiolabeled with carbon-11 and the resulting positron-emission tomography (PET) tracer [C]MK-7246 was evaluated in a pig model and in vitro cell lines.
View Article and Find Full Text PDFAntibodies are attractive as radioligands due to their outstanding specificity and high affinity, but their inability to cross the blood-brain barrier (BBB) limits their use for CNS targets. To enhance brain distribution, amyloid-β (Aβ) antibodies were fused to a transferrin receptor (TfR) antibody fragment, enabling receptor mediated transport across the BBB. The aim of this study was to label these bispecific antibodies with fluorine-18 and use them for Aβ PET imaging.
View Article and Find Full Text PDFAn increased resistance to surgical site infections has been associated with surgical meshes composed of naturally occurring materials, including poly-4-hydroxybutrate (4HB). 4HB is a naturally occurring short-chain fatty acid that has been shown to promote endogenous expression of the Cramp gene coding for the antimicrobial peptide (AMP) cathelicidin LL-37 in murine bone marrow-derived macrophages. The molecular pathways involved in the 4HB-induced cathelicidin LL-37 expression have not yet been identified.
View Article and Find Full Text PDFAromatase, the enzyme that in the brain converts testosterone and androstenedione to estradiol and estrone, respectively, is a putative key factor in psychoneuroendocrinology. In vivo assessment of aromatase was performed to evaluate tracer kinetic models and optimal scan duration, for quantitative analysis of the aromatase positron emission tomography (PET) ligand [ C]cetrozole. Anatomical magnetic resonance and 90-min dynamic [ C]cetrozole PET-CT scans were performed on healthy women.
View Article and Find Full Text PDFThe prospects for using carbon-11 labelled compounds in molecular imaging has improved with the development of diverse synthesis methods, including C-carbonylations and refined techniques to handle [C]carbon monoxide at a nanomole scale. Facilitating biological research and molecular imaging was the driving force when [C]carbon monoxide was used in the first in vivo application with carbon-11 in human (1945) and when [C]carbon monoxide was used for the first time as a chemical reagent in the synthesis of [C]phosgene (1978). This review examines a rich plethora of labelled compounds synthesized from [C]carbon monoxide, their chemistry and use in molecular imaging.
View Article and Find Full Text PDFIntroduction: [C]UCB-J is a tracer developed for PET (positron emission tomography) that has high affinity towards synaptic vesicle glycoprotein 2A (SV2A), a protein believed to participate in the regulation of neurotransmitter release in neurons and endocrine cells. The localisation of SV2A in the synaptic terminals makes it a viable target for in vivo imaging of synaptic density in the brain. Several SV2A targeting compounds have been evaluated as PET tracers, including [C]UCB-J, with the aim to facilitate studies of synaptic density in neurological diseases.
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