Preclinical Evaluation of Novel PET Probes for Dementia.

Inflammation involves the activation of innate immune cells and is believed to play an important role in the development and progression of both infectious and non-infectious diseases such as neurodegeneration, autoimmune diseases, pulmonary and cancer. Inflammation in the brain is marked by the upregulation of translocator protein (TSPO) in microglia. High TSPO levels are also found, for example, in macrophages in cases of rheumatoid arthritis and in malignant tumor cells compared to their relatively low physiological expression. The same applies for cyclooxgenase-2 (COX-2), which is constitutively expressed in the kidney, brain, thymus and gastrointestinal tract, but induced in microglia, macrophages and synoviocytes during inflammation. This puts TSPO and COX-2 in the spotlight as important targets for the diagnosis of inflammation. Imaging modalities, such as positron emission tomography and single-photon emission tomography, can be used to localize inflammatory processes and to track their progression over time. They could also enable the monitoring of the efficacy of therapy and predict its outcome. This review focuses on the current development of PET and SPECT tracers, not only for the detection of neuroinflammation, but also for emerging diagnostic measures in infectious and other non-infectious diseases such as rheumatic arthritis, cancer, cardiac inflammation and in lung diseases.

Radiotracers for Imaging of Inflammatory Biomarkers TSPO and COX-2 in the Brain and in the Periphery

The translocator protein 18 kDa (TSPO) is an evolutionarily conserved mitochondrial transmembrane protein implicated in various neuropathologies and inflammatory conditions, making it a longstanding diagnostic and therapeutic target of interest. Despite the development of various classes of TSPO ligand chemotypes, and the elucidation of bacterial and non-human mammalian experimental structures, many unknowns exist surrounding its differential structural and functional features in health and disease. There are several limitations associated with currently used computational methodologies for modelling the native structure and ligand-binding behaviour of this enigmatic protein. In this perspective, we provide a critical analysis of the developments in the uses of these methods, outlining their uses, inherent limitations, and continuing challenges. We offer suggestions of unexplored opportunities that exist in the use of computational methodologies which offer promise for enhancing our understanding of the TSPO. 

Structure-Based Drug Design for TSPO: Challenges and Opportunities.

Positron emission tomography (PET) is a non-invasive imaging technology that can reveal molecular alterations in the brains of Alzheimer's disease (AD) patients with high sensitivity and specificity, which is crucial for clinical diagnosis, disease staging, and monitoring potential therapeutic approaches. Several biomarkers contribute to the clinical diagnosis of AD, and according to the evolving ATX(N) framework, these biomarkers can be classified into the amyloid-β (A) pathway, Tau-mediated pathophysiology (T), neurodegeneration (N), and other related molecular and cellular network changes in the AD continuum (X), such as neuroinflammation, synaptic dysfunction, and neurochemical deficits. This review provides an overview of PET tracers reported for several typical and classical targets in early AD diagnosis and compares tracers targeting the same biomarkers. We believe this review will support and facilitate progress in early AD diagnosis and further propose the future potential of both PET tracers and targets. 

Current status of PET tracers for the early diagnosis of Alzheimer's disease

Abstract Purpose : 18 F-SF51 was previously found to have high binding affinity and selectivity for 18kDa translocator protein (TSPO) in mouse brain. This study sought to further evaluate the suitability of 18 F-SF51 for absolute quantification of TSPO in monkey brain. Methods: Positron emission tomography (PET) imaging was performed in monkey brain (n=3) at baseline and after pre-blockade with the TSPO ligands PK11195 and PBR28. TSPO binding was calculated as total distribution volume corrected for free parent fraction in plasma ( V T / f P ) using a two-tissue compartment model. Receptor occupancy and nondisplaceable uptake were determined via Lassen plot. Binding potential ( BP ND ) was calculated as the ratio of specific binding to nondisplaceable uptake. Time stability of V T was used as an indirect probe to detect radiometabolite accumulation in the brain. In vivo and ex vivo experiments were performed in mice to determine the distribution of the radioligand. Results: After 18 F-SF51 injection, the concentration of brain radioactivity peaked at 2.0 standardized uptake value (SUV) at ~10 minutes and declined to 30% of the peak at 180 minutes. V T / f P at baseline was generally high (203±15 mL· cm -3 ) and decreased by ~90% after blockade with PK11195. BP ND of the whole brain was 7.6 ± 4.3. V T values reached levels similar to terminal 180-minute values by 70 minutes and remained relatively stable thereafter with excellent identifiability (standard errors &lt; 5%), suggesting that no significant radiometabolites accumulated in the brain. Ex vivo experiments in mouse brain showed that 96% of radioactivity was parent. No significant uptake was observed in the skull, suggesting a lack of defluorination in vivo. Conclusion: The results demonstrate that 18 F-SF51 is an excellent radioligand with a good ratio of specific to nondisplaceable uptake as well as good time stability of total receptor binding. Collectively, the results suggest that 18 F-SF51 warrants further evaluation in humans. 

/pdf/in-vivo-evaluation-of-a-novel-18f-labeled-pet-radioligand-fcpqsnox.pdf

In vivo evaluation of a novel 18F-labeled PET radioligand for translocator protein 18kDa (TSPO) in monkey brain

[11C]ER176 has adequate sensitivity to image the human brain translocator protein (TSPO) in all three genotypes by positron emission tomography (PET). However, its clinical application is limited by the short half-life of 11C (20.38 min). To overcome the deficiency of [11C]ER176 and keep the pharmacophore features of ER176 to the maximum extent, we designed four fluorine-labeled ER176 derivatives using the deuterium method. In vitro competition binding confirmed that the designed compounds had high affinity for TSPO. Biodistribution experiments showed that tissues with high expression of TSPO had high uptake of these compounds, as well as that the compound showed high brain penetration and mild defluorination in vivo. Therefore, [18F]BIBD-239 with simple synthesis conditions was selected for further biological evaluation. Theoretical simulations showed that BIBD-239 and ER176 have similar binding modes and sites to Ala147-TSPO and Thr147-TSPO, which indicated that the tracers may have consistent sensitivity to the three affinity genotypes. In vitro autoradiography and in vivo PET studies of the ischemic rat brain showed dramatically higher uptake of [18F]BIBD-239 on the lesion site compared to the contralateral side with good brain kinetics. Additionally, [18F]BIBD-239 provided clear tumor PET images in a GL261 glioma model. Importantly, PET imaging and liquid chromatography-high-resolution mass spectrometry (LC-HRMS) results showed that in vivo defluorination and other metabolites of [18F]BIBD-239 did not interfere with brain imaging. Conclusively, [18F]BIBD-239, similar to ER176 with low polymorphism sensitivity, has simple labeling conditions, high labeling yield, high affinity, and high specificity for TSPO, and it is planned for further evaluation in higher species.

[18F]BIBD-239: 18F-Labeled ER176, a Positron Emission Tomography Tracer Specific for the Translocator Protein.

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[18F]BIBD-239: 18F-Labeled ER176, a Positron Emission Tomography Tracer Specific for the Translocator Protein.