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

We designed and synthesized deuterium-substituted [18F]fluoromethyl-PBR28 ([18F]1-d2) as a novel translocator protein 18 kDa (TSPO)-targeted radioligand with enhanced in vivo stability. The comparison studies between [18F]fluoromethyl-PBR28 ([18F]1) and its deuterate analog ([18F]1-d2) 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, [18F]1-d2 provided significantly lower femur uptake than [18F]1 (1.5 ± 1.2 vs. 4.1 ± 1.7%ID/g at 2 h post-injection) in an ex vivo biodistribution study. [18F]1-d2 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 (BPND = 3.17 ± 0.48), in a LPS-induced acute neuroinflammation rat model, comparable to that of [18F]1 (BPND = 2.13 ± 0.51). These results indicate that [18F]1-d2 had higher in vivo stability, which resulted in an enhanced target-to-background ratio compared to that induced by [18F]1.

Moon BS ，Jung JH ，Park HS ，Contino M ，Denora N ，Lee BC ，Kim SE ... -  《-》

A Novel PET Imaging Probe for the Detection and Monitoring of Translocator Protein 18 kDa Expression in Pathological Disorders.

Perrone M ，Moon BS ，Park HS ，Laquintana V ，Jung JH ，Cutrignelli A ，Lopedota A ，Franco M ，Kim SE ，Lee BC ，Denora N ... -  《Scientific Reports》

[(18)F]Fluoromethyl-PBR28 as a potential radiotracer for TSPO: preclinical comparison with [(11)C]PBR28 in a rat model of neuroinflammation.

Moon BS ，Kim BS ，Park C ，Jung JH ，Lee YW ，Lee HY ，Chi DY ，Lee BC ，Kim SE ... -  《-》

Synthesis of 6-[¹⁸F]fluoro-PBR28, a novel radiotracer for imaging the TSPO 18 kDa with PET.

6-Fluoro-PBR28 (N-(6-fluoro-4-phenoxypyridin-3-yl)-N-(2-methoxybenzyl)acetamide), a fluorinated analogue of the recently developed TSPO 18 kDa ligand PBR28, was synthesized and labelled with fluorine-18. 6-Fluoro-PBR28 and its 6-chloro/6-bromo counterparts were synthesized in six chemical steps and obtained in 16%, 10% and 19% overall yields, respectively. Labelling with fluorine-18 was performed in one single step (chlorine/bromine-for-fluorine heteroaromatic substitution) using a Zymate-XP robotic system affording HPLC-purified, ready-to-inject, 6-[(18)F]fluoro-PBR28 (>95% radiochemically pure). Non-decay-corrected overall yields were 9-10% and specific radioactivities ranged from 74 to 148 GBq/μmol. In vitro binding experiments, dynamic μPET studies performed in a rat model of acute neuroinflammation (unilaterally, AMPA-induced, striatum-lesioned rats) and ex vivo autoradiography on the same model demonstrated the potential of 6-[(18)F]fluoro-PBR28 to image the TSPO 18 kDa using PET.

Damont A ，Boisgard R ，Kuhnast B ，Lemée F ，Raggiri G ，Scarf AM ，Da Pozzo E ，Selleri S ，Martini C ，Tavitian B ，Kassiou M ，Dollé F ... -  《-》

Evaluation of the novel TSPO radiotracer 2-(7-butyl-2-(4-(2-([(18)F]fluoroethoxy)phenyl)-5-methylpyrazolo[1,5-a]pyrimidin-3-yl)-N,N-diethylacetamide in a preclinical model of neuroinflammation.

Translocator Protein (18 kDa, TSPO) is regarded as a useful biomarker for neuroinflammation imaging. TSPO PET imaging could be used to understand the role of neuroinflammation in brain diseases and as a tool for evaluating novel therapeutic effects. As a promising TSPO probe, [18F]DPA-714 is highly specific and offers reliable quantification of TSPO in vivo. In this study, we further radiosynthesized and evaluated another novel TSPO probe, 2-(7-butyl-2-(4-(2-[18F]fluoroethoxy)phenyl)-5-methylpyrazolo[1,5-a]pyrimidin-3-yl)-N,N-diethylacetamide ([18F]VUIIS1018A), which features a 700-fold higher binding affinity for TSPO than that of [18F]DPA-714. We evaluated the performance of [18F]VUIIS1018A using dynamic in vivo PET imaging, radiometabolite analysis, in vitro autoradiography assays, biodistribution analysis, and blocking assays. In vivo study using this probe demonstrated high signal-to-noise ratio, binding potential (BPND), and binding specificity in preclinical neuroinflammation studies. Taken together, these findings indicate that [18F]VUIIS1018A may serve as a novel TSPO PET probe for neuroinflammation imaging.

Tang D ，Fujinaga M ，Hatori A ，Zhang Y ，Yamasaki T ，Xie L ，Mori W ，Kumata K ，Liu J ，Manning HC ，Huang G ，Zhang MR ... -  《-》