Flutriciclamide (¹⁸F-GE180) PET: First-in-Human PET Study of Novel Third-Generation In Vivo Marker of Human Translocator Protein

Abstract

Neuroinflammation is associated with neurodegenerative disease. PET radioligands targeting the 18-kDa translocator protein (TSPO) have been used as in vivo markers of neuroinflammation, but there is an urgent need for novel probes with improved signal-to-noise ratio. Flutriciclamide ( 18 F-GE180) is a recently developed thirdgeneration TSPO ligand. In this first study, we evaluated the optimum scan duration and kinetic modeling strategies for 18 F-GE180 PET in (older) healthy controls. Methods: Ten healthy controls, 6 TSPO high-affinity binders, and 4 mixed-affinity binders were recruited. All subjects underwent detailed neuropsychologic tests, MRI, and a 210-min 18 F-GE180 dynamic PET/CT scan using metabolite-corrected arterial plasma input function. We evaluated 5 different kinetic models: irreversible and reversible 2-tissue-compartment models, a reversible 1-tissue model, and 2 models with an extra irreversible vascular compartment. The minimal scan duration was established using 210-min scan data. The feasibility of generating parametric maps was also investigated using graphical analysis. Results: 18 F-GE180 concentration was higher in plasma than in whole blood during the entire scan duration. The volume of distribution (V T ) was 0.17 in high-affinity binders and 0.12 in mixed-affinity binders using the kinetic model. The model that best represented brain 18 F-GE180 kinetics across regions was the reversible 2-tissue-compartment model (2TCM4k), and 90 min resulted as the optimum scan length required to obtain stable estimates. Logan graphical analysis with arterial input function gave a V T highly consistent with V T in the kinetic model, which could be used for voxelwise analysis. Conclusion: We report for the first time, to our knowledge, the kinetic properties of the novel third-generation TSPO PET ligand 18 F-GE180 in humans: 2TCM4k is the optimal method to quantify the brain uptake, 90 min is the optimal scan length, and the Logan approach could be used to generate parametric maps. Although these control subjects have shown relatively low V T , the methodology presented here forms the basis for quantification for future PET studies using 18 F-GE180 in different pathologies.

Translocator Protein-18 kDa (TSPO) Positron Emission Tomography (PET) Imaging and Its Clinical Impact in Neurodegenerative Diseases

“…The fact that the second-generation radiopharmaceuticals have been found to be sensitive to this polymorphism leads searchers to develop rs6971-insensitive radioligands. These rs6971-insensitive radioligands, called third generation TSPO tracers, include 11 C-ER176 [41] and flutriciclamide ( 18 F-GE180) [42]. Nonetheless, the clinical relevance of these compounds remains to be confirmed [41].…”

TSPO PET Imaging: From Microglial Activation to Peripheral Sterile Inflammatory Diseases?

“…The fact that the second-generation radiopharmaceuticals have been found to be sensitive to this polymorphism leads searchers to develop rs6971-insensitive radioligands. For this purpose, 18 F-GE180, a third-generation TSPO tracers, was evaluated and seemed to be less sensitive to the TSPO-binding affinity status than the second generation [51]. Unfortunately, the small sample size and the exclusion of the LAB from this preliminary study leaded do not allow concluding that 18 F-GE180 is insensitive to the polymorphism.…”

Radiosynthesis of (R,S)‐[18F]GE387: A Potential PET Radiotracer for Imaging Translocator Protein 18 kDa (TSPO) with Low Binding Sensitivity to the Human Gene Polymorphism rs6971

“…[8] This radiotracer has now been evaluated in humans for imaging TSPO expression. [9][10][11][12] However,w hile [ 18 F]5 demonstrated less dependence than other second-generation tracers on the single nucleotidep olymorphism, its affinity for TSPO still differs significantly amongst the three binding groups (binding affinity ratio LABs/HABs = 5.1). [13] Therefore, there is still an eed to develop aT SPO radiotracer with low sensitivity toward this polymorphism.…”