Abstract
A new fluorine-substituted ligand, compound 1 (CB251), with a very high affinity (Ki = 0.27 ± 0.09 nM) and selectivity for the 18-kDa translocator protein (TSPO), is presented as an attractive biomarker for the diagnosis of neuroinflammation, neurodegeneration and tumour progression. To test compound 1 as a TSPO PET imaging agent in vivo, 2-(2-(4-(2-[18F]fluoroethoxy)phenyl)-6,8-dichloroimidazo[1,2-a]pyridin-3-yl)-N,N-dipropylacetamide ([18F]1; [18F]CB251) was synthesized by nucleophilic aliphatic substitution in a single-step radiolabelling procedure with a 11.1 ± 3.5% (n = 14, decay corrected) radiochemical yield and over 99% radiochemical purity. In animal PET imaging studies, [18F]CB251 provided a clearly visible image of the inflammatory lesion with the binding potential of the specifically bound radioligand relative to the non-displaceable radioligand in tissue (BPND 1.83 ± 0.18), in a neuroinflammation rat model based on the unilateral stereotaxic injection of lipopolysaccharide (LPS), comparable to that of [11C]PBR28 (BPND 1.55 ± 0.41). [18F]CB251 showed moderate tumour uptake (1.96 ± 0.11%ID/g at 1 h post injection) in human glioblastoma U87-MG xenografts. These results suggest that [18F]CB251 is a promising TSPO PET imaging agent for neuroinflammation and TSPO-rich cancers.
Highlights
Microglia constitute up to 10% of the total cell population of the brain and make up the largest resident population of macrophages, which play an important role in the pathogenesis of several neurodegenerative disorders
We recently proposed a practical and easy approach to achieve this objective using fluorescent probes chemically linked to 2-phenyl-imidazo[1,2-a]pyridine acetamide translocator protein kDa (TSPO) ligands[12,13]
Our initial strategy was to synthesize various potent and selective PBR ligands mainly characterized by various substituents at 6- and 8-positions of the imidazo[1,2-a]pyridine nucleus and several molecules in spired by the novel imidazopyridine acetamides such as N-[11C]methylated imidazopyridine acetamides ([11C]CB148), [11C]CB184 and [11C]CB190 with improved in vivo specificity for TSPO were investigated[11,18,19]
Summary
Microglia constitute up to 10% of the total cell population of the brain and make up the largest resident population of macrophages, which play an important role in the pathogenesis of several neurodegenerative disorders. Potent ligands for TSPO have been identified from many different structural classes, such as isoquinoline carboxamides (e.g., PK 11195)[7], benzodiazepines (e.g., Ro-54864)[8], phenoxyarylacetamides (e.g., DAA1106)[9], aryloxyanilides (e.g., PBR28)[10] and 2-phenyl-imidazo[1,2-a]pyridine acetamides (e.g., alpidem)[11] Many of these ligands have been developed to visualize activated microglia via several imaging techniques. Through our efforts to develop new TSPO ligands, we report the synthesis and in vitro and in vivo evaluation of the novel 18F-labelled 2-phenyl-imidazo[1,2-a]pyridine analogue [18F]1, named [18F] CB251, as a TSPO-selective PET radiotracer that is useful for imaging activated microglia, as well as TSPO-rich brain tumours Through our efforts to develop new TSPO ligands, we report the synthesis and in vitro and in vivo evaluation of the novel 18F-labelled 2-phenyl-imidazo[1,2-a]pyridine analogue [18F]1, named [18F] CB251 in Fig. 1, as a TSPO-selective PET radiotracer that is useful for imaging activated microglia, as well as TSPO-rich brain tumours
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