In vitro Characterization of the Regional Binding Distribution of Amyloid PET Tracer Florbetaben and the Glia Tracers Deprenyl and PK11195 in Autopsy Alzheimer’s Brain Tissue

Abstract

Background: Emerging evidence indicates a central role of gliosis in Alzheimer’s disease (AD) pathophysiology. However, the regional distribution and interaction of astrogliosis and microgliosis in association with amyloid-β (Aβ) still remain uncertain. Objective: Here we studied the pathological profiles in autopsy AD brain by using specific imaging tracers. Methods: Autopsy brain tissues of AD (n = 15, age 70.4±8.5 years) and control cases (n = 12, age 76.6±10.9) were examined with homogenate binding assays, autoradiography for Aβ plaques (3H-florbetaben/3H-PIB), astrogliosis (3H-L-deprenyl), and microgliosis (3H-PK11195/3H-FEMPA), as well as immunoassays. Results: In vitro saturation analysis revealed high-affinity binding sites of 3H-florbetaben, 3H-L-deprenyl, and 3H-PK11195/3H-FEMPA in the frontal cortex of AD cases. In vitro 3H-florbetaben binding increased across cortical and subcortical regions of AD compared to control with the highest binding in the frontal and parietal cortices. The in vitro 3H-L-deprenyl binding showed highest binding in the hippocampus (dentate gyrus) followed cortical and subcortical regions of AD while the GFAP expression was upregulated only in the hippocampus compared to control. The in vitro 3H-PK11195 binding was solely increased in the parietal cortex and the hippocampus of AD compared to control. The 3H-florbetaben binding positively correlated with the 3H-L-deprenyl binding in the hippocampus and parietal cortex of AD and controls. Similarly, a positive correlation was observed between 3H-florbetaben binding and GFAP expression in hippocampal AD and control brain. Conclusion: The use of multi-modal imaging tracers revealed different regional pattern of changes in autopsy AD brain with respect to amyloid plaque pathology versus astrogliosis and microgliosis.

PET Imaging of Neuroinflammation in Alzheimer’s Disease

“…However, recent clinical study with [ 11 C]ER176 ( 105 ) and [ 11 C]GE-180 ( 88 ) demonstrated a significant decrease in ligand retention in low-affinity binders, suggesting the necessity of further in vivo examination. Second, the heterogenous cellular sources of TSPO PET tracers have been demonstrated in astrocytes, endothelial cells, and vascular smooth muscle cells, in addition to microglia in both patients with AD and animal models ( 61 , 85 , 86 , 193 , 226 – 229 ) ( Figures 1A, B ) . Although conventional opinions consider microglia as major cellular source of TSPO in the central nervous system, latest study finds vascular TSPO provides major binding sites for TSPO ligands including most widely used [ 11 C]PK11195 and [ 11 C]PBR28 in normal mouse brains ( 57 ).…”

“…A few second generation tracers including [ 11 C]DAA1106, [ 1( F]FEDAA1106, [ 125 I]CLINDE [ 11 C]PBR06, [ 11 C]PBR28, [ 18 F]PBR111, [ 18 F]DPA-713, [ 18 F]DPA-714, [ 18 F]F-DPA, [ 11 C]AC-5216, [ 18 F]FEMPA, and [ 18 F]FEPPA have been developed to overcome the limitations of [ 11 C]PK11195 ( 45 , 46 , 52 , 61 – 63 , 66 , 69 – 71 , 83 , 84 , 197 ) ( Table 1 ). However, the binding affinities of second generation TSPO tracers in human brain differ based on the rs6971 polymorphisms, which introduces higher variability between subjects ( 45 , 46 , 52 , 61 – 63 , 66 , 69 – 71 , 197 ). In addition, the [ 11 C]PBR28 binding appears to be affected by chromosome 1 variant rs2997325 on microglial activation ( 198 ).…”

“…Irreversible MAO-B inhibitors [ 11 C]deuterium-L-deprenyl (DED) have been used in PET imaging studies and demonstrated early astrocytosis in sporadic and autosomal dominant AD patients ( 61 , 156 – 161 , 163 ) and in amyloidosis mouse models ( 163 , 164 ). [ 18 F]fluorodeprenyl-D 2 showed favorable kinetic properties with relatively fast washout from non-human primate brain and improved sensitivity for MAO-B imaging ( 165 ).…”

In-vitro and in-vivo characterization of CRANAD-2 for multi-spectral optoacoustic tomography and fluorescence imaging of amyloid-beta deposits in Alzheimer mice

“…Though, we observed a percentage of binding to bovine serum albumin that is a plasma protein in the circulation and found in Aβ plaques. This is a common phenomenon of Aβ binding probes such as BTA-1, PIB, florbetaben, florbetapir etc [ [71] , [72] , [73] , [74] ]. Co-staining of CRANAD-2 to brain sections from arcAβ mice with 6E10/OC antibodies of Aβ deposition clearly showed close resemblance in both vascular and parenchymal Aβ deposits.…”

In vivo Imaging of Cannabinoid Type 2 Receptors: Functional and Structural Alterations in Mouse Model of Cerebral Ischemia by PET and MRI

“…Translocator protein (TSPO) is the most widely used neuroinflammation target for PET imaging. [16][17][18][19][20][21][22][23][24][25][26][27], have been evaluated in (pre-)clinical studies. PET imaging studies using TSPO tracers have shown increased brain uptake in post-stroke, although different time course and distribution were detected depending on the animal models and procedures.…”