We designed and synthesized deuterium-substituted [ 18 F]fluoromethyl-PBR28 ([ 18 F]1-d 2 ) as a novel translocator protein 18 kDa (TSPO)-targeted radioligand with enhanced in vivo stability. The comparison studies between [ 18 F]fluoromethyl-PBR28 ([ 18 F]1) and its deuterate analog ([ 18 F]1-d 2 ) were investigated in terms of in vitro binding affinity, lipophilicity and in vivo stability. In addition, the accuracies of both radioligands were determined by comparing the PET imaging data in the same LPS-induced neuroinflammation rat model. Both aryloxyanilide analogs showed similar lipophilicity and in vitro affinity for TSPO. However, [ 18 F]1-d 2 provided significantly lower femur uptake than [ 18 F]1 (1.5 ± 1.2 vs. 4.1 ± 1.7%ID/g at 2 h post-injection) in an ex vivo biodistribution study. [ 18 F]1-d 2 was also selectively accumulated in the inflammatory lesion with the binding potential of the specifically bound radioligand relative to the non-displaceable radioligand in tissue (BP ND = 3.17 ± 0.48), in a LPS-induced acute neuroinflammation rat model, comparable to that of [ 18 F]1 (BP ND = 2.13 ± 0.51). These results indicate that [ 18 F]1-d 2 had higher in vivo stability, which resulted in an enhanced target-to-background ratio compared to that induced by [ 18 F]1.

Preclinical comparison study between [ 18 F]fluoromethyl-PBR28 and its deuterated analog in a rat model of neuroinflammation

Contino, Marialessandra;Denora, Nunzio;
2018

Abstract

We designed and synthesized deuterium-substituted [ 18 F]fluoromethyl-PBR28 ([ 18 F]1-d 2 ) as a novel translocator protein 18 kDa (TSPO)-targeted radioligand with enhanced in vivo stability. The comparison studies between [ 18 F]fluoromethyl-PBR28 ([ 18 F]1) and its deuterate analog ([ 18 F]1-d 2 ) were investigated in terms of in vitro binding affinity, lipophilicity and in vivo stability. In addition, the accuracies of both radioligands were determined by comparing the PET imaging data in the same LPS-induced neuroinflammation rat model. Both aryloxyanilide analogs showed similar lipophilicity and in vitro affinity for TSPO. However, [ 18 F]1-d 2 provided significantly lower femur uptake than [ 18 F]1 (1.5 ± 1.2 vs. 4.1 ± 1.7%ID/g at 2 h post-injection) in an ex vivo biodistribution study. [ 18 F]1-d 2 was also selectively accumulated in the inflammatory lesion with the binding potential of the specifically bound radioligand relative to the non-displaceable radioligand in tissue (BP ND = 3.17 ± 0.48), in a LPS-induced acute neuroinflammation rat model, comparable to that of [ 18 F]1 (BP ND = 2.13 ± 0.51). These results indicate that [ 18 F]1-d 2 had higher in vivo stability, which resulted in an enhanced target-to-background ratio compared to that induced by [ 18 F]1.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11586/227437
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