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Fluorine-18 click radiosynthesis and MicroPET/CT evaluation of a small peptide-a potential PET probe for carbonic anhydrase IX
摘要： Carbonic anhydrase IX (CA IX) is the first carbonic anhydrase found to be associated with cancer that is over-expressed in a variety of human solid tumors. As a surrogate marker for hypoxia, the expression of CA IX is strongly upregulated in hypoxic tumors by hypoxia and hypoxia-inducible factor 1a (HIF-1a). In our pursuit of a CA IX-specific PET probe, we designed and synthesized a peptide-based CA IX imaging probe by the efficient click reaction of 1,3-dipolar cycloaddition of terminal alkynes and organic azides. The probe 18F-CA IX-P1-4-10 was obtained with a radiochemical yield of 35-45% (n = 5) and radiochemical purity of >99% in 70-80 min (HPLC purification time included). 18F-CAIX-P1-4-10 had good stability in phosphate buffered saline (PBS), but about 51% peptide degradation was detected in new-born calf serum (NBCS) after incubation. Preliminary microPET/CT experiments demonstrated a specific uptake of 18F-CA IX-P1-4-10 in HT29 tumor and the uptake of 18F-CA IX-P1-4-10 was blocked by peptide CA IX-P1-4-10-Yne pretreatment. Immunohistochemical staining and western blotting studies confirmed the HT29 tumor was CA IX-positive which further proved tumor accumulation of 18F-CA IX-P1-4-10 was correlated with CA IX expression. The results suggest that 18F-CA IX-P1-4-10 is a promising PET tracer for the specific imaging of CA IX-expressing tumors at the molecular level.
关键词： peptide,tumor hypoxia,18F-labeling,Carbonic anhydrase IX,PET imaging
更新于2025-09-19 17:15:36
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Synthesis and Preliminary Evaluations of a Triazole-cored Antagonist ([18F]N2B-0518) as PET Imaging Probe for GluN2B Subunit in the Brain
摘要： GluN2B is the most studied subunit of N-methyl-D-aspartate receptors (NMDARs) and implicated in the pathologies of various central nervous system disorders and neurodegenerative diseases. As pan NMDAR antagonists often produce debilitating side effects, new approaches in drug discovery have shifted to subtype-selective NMDAR modulators, especially GluN2B-selective antagonists. While positron emission tomography (PET) studies of GluN2B-selective NMDARs in the living brain would enable target engagement in drug development and improve our understanding in the NMDAR signaling pathways between normal and disease conditions, a suitable PET ligand is yet to be identified. Herein we developed an 18F-labeled potent antagonist, 2-((1-(4-[18F]fluoro-3-methylphenyl)-1H-1,2,3-triazol-4-yl)methoxy)-5-methoxypyrimidine ([18F]13; also called [18F]N2B-0518) as a PET tracer for imaging the GluN2B subunit. The radiofluorination of [18F]13 was efficiently achieved by our spirocyclic iodonium ylide (SCIDY) method. In in vitro autoradiography studies, [18F]13 displayed highly region-specific binding in brain sections of rat and non-human primate, which was in accordance with the expression of GluN2B subunit. Ex vivo biodistribution in mice revealed that [18F]13 could penetrate the blood-brain barrier with moderate brain uptake (3.60% ID/g at 2 min) and rapid washout. Altogether, this work provides a GluN2B-selective PET tracer bearing new chemical scaffold and shows high specificity to GluN2B subunit in vitro, which may pave the way for the development of a new generation of GluN2B PET ligands.
关键词： subtype-selective,PET imaging,18F-labeling,autoradiography,GluN2B subunit,spirocyclic iodonium ylide
更新于2025-09-19 17:15:36