Evaluation of the novel TSPO radiotracer [18F] VUIIS1008 in a preclinical model of cerebral ischemia in rats

Abstract

BackgroundIn vivo positron-emission tomography (PET) imaging of transporter protein (TSPO) expression is an attractive and indispensable tool for the diagnosis and therapy evaluation of neuroinflammation after cerebral ischemia. Despite several radiotracers have shown an excellent capacity to image neuroinflammation, novel radiotracers such as [18F] VUIIS1008 have shown promising properties to visualize and quantify the in vivo expression of TSPO.MethodsLongitudinal in vivo magnetic resonance (MRI) and PET imaging studies with the novel TSPO radiotracer 2-(5,7-diethyl-2-(4-(2-[18F] fluoroethoxy) phenyl) pyrazolo [1,5-a] pyrimidin-3-yl)-N, N-diethylacetamide ([18F] VUIIS1008), and (N, N-diethyl-2-(2-[4-(2-fluoroethoxy)-phenyl]-5,7-dimethyl-pyrazolo [1,5-a] yrimidin-3-yl)-acetamide ([18F] DPA-714) were carried out before and at days 1, 3, 7, 14, 21, and 28 following the transient middle cerebral artery occlusion (MCAO) in rats.ResultsMRI images showed the extension and evolution of the brain infarction after ischemic stroke in rats. PET imaging with [18F] VUIIS1008 and [18F] DPA714 showed a progressive increase in the ischemic brain hemisphere during the first week, peaking at day 7 and followed by a decline from days 14 to 28 after cerebral ischemia. [18F] DPA714 uptake showed a mild uptake increase compared to [18F] VUIIS1008 in TSPO-rich ischemic brain regions. In vivo [18F] VUIIS1008 binding displacement with VUIIS1008 was more efficient than DPA714. Finally, immunohistochemistry confirmed a high expression of TSPO in microglial cells at day 7 after the MCAO in rats.ConclusionsAltogether, these results suggest that [18F] VUIIS1008 could become a valuable tool for the diagnosis and treatment evaluation of neuroinflammation following ischemic stroke.

Diagnostic and Therapeutic Potential of TSPO Studies Regarding Neurodegenerative Diseases, Psychiatric Disorders, Alcohol Use Disorders, Traumatic Brain Injury, and Stroke: An Update

“…18F-GE-180 uptake was 24% higher in the core of the ischemic lesion and 18% lower in the contralateral healthy tissue than that of 11C-PK11195 uptake (i.e., a 1.5 ± 0.2-fold higher signal to noise ratio) [186]. Following transient middle cerebral artery occlusion (MCAO) in rats, longitudinal in vivo magnetic resonance (MRI) and PET imaging studies were carried out with the novel TSPO radiotracer 2-18F-VUIIS1008 99 N-diethylacetamide (18F-VUIIS1008), and 18F-DPA-714 (full name: (N, N-diethyl-2-(2-[4-(2-fluoroethoxy)-phenyl]-5,7-dimethyl-pyrazolo[1,5-a]yrimidin-3-yl)-acetamide)) [187]. 18F-PA714 uptake showed a mild uptake increase compared to 18F-VUIIS1008 in TSPO-rich ischemic brain regions [187].…”

“…Following transient middle cerebral artery occlusion (MCAO) in rats, longitudinal in vivo magnetic resonance (MRI) and PET imaging studies were carried out with the novel TSPO radiotracer 2-18F-VUIIS1008 99 N-diethylacetamide (18F-VUIIS1008), and 18F-DPA-714 (full name: (N, N-diethyl-2-(2-[4-(2-fluoroethoxy)-phenyl]-5,7-dimethyl-pyrazolo[1,5-a]yrimidin-3-yl)-acetamide)) [187]. 18F-PA714 uptake showed a mild uptake increase compared to 18F-VUIIS1008 in TSPO-rich ischemic brain regions [187]. Combined with other studies, it appears that 18F-GE-180 is more effective than both 18F-DPA714 and 18F-VUIIS1008.…”

Cellular Sources and Regional Variations in the Expression of the Neuroinflammatory Marker Translocator Protein (TSPO) in the Normal Brain

“…Much of the interest in TSPO in the central nervous system has been based on the observation that injury or progressive disease induces a marked upregulation of TSPO in mitochondria of microglia upon their transition from a resting to an activated state [ 2 , 6 ]. The subsequent development of radioligands for TSPO has given rise to a field of molecular imaging aimed at detecting activated microglia, often generically referred to as “neuroinflammation” in neurological disorders [ 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 ] and also psychiatric illnesses [ 15 , 16 , 17 , 18 , 19 , 20 ]. The term “neuroinflammation” has become a generic term that does not distinguish between a local immune response and microglial activation in the wake of neural or other injury [ 21 ].…”

[18F]VUIIS1009B Features a Superior Imaging Performance to [18F]DPA-714 in TSPO Density Characterization for Neuroinflammatory PET Imaging

“…In this study, the in vivo PET imaging and in vitro autoradiographic results con rmed increase in provides accurate informative information of the expression and distribution of TSPO activity after cerebral ischemia [33] . Similarly, Pulagam et al also demonstrated the feasibility to use [ 18 F]VUIIS1008 to monitor TSPO expression longitudinally in a rat model of cerebral ischemia, with the results suggesting 18 F-VUIIS1008 could become a valuable tool for the diagnosis and treatment evaluation of neuroin ammation following ischemic stroke [38] . Furthermore, Golla et al used multiple methods to generate the quantitative images for [ 18 F]DPA-714 in a clinic study with healthy subjects and AD patients participated [40] .…”

“…In the longitudinal studies of neurological diseases, TSPO density evaluation with different radiotracers and analytical approaches have been performed to increase the sensitivity of TSPO expression characterization, and thus to elucidate the relationship between the disease progression and TSPO density [34][35][36][37] . In these studies, semi-quantitative parameters like %ID/cc and SUV are widely evaluated in both clinical and preclinical studies [33,38] . Compared to the semi-quantitative parameters, macro parameters (like BP ND , DVR, V T ) can provide more detailed information on radiotracer pharmacokinetics and TSPO expression, which is more meaningful in longitudinal monitoring of neuroin ammatory diseases [39] .…”