Cerebral Nicotinic Acetylcholine Receptors (nAChRs) In Early Alzheimer’s Disease (AD) Assessed With The New Radioligand [18F]Flubatine and PET

Objectives: There is evidence from post-mortem studies that the loss of nAChRs, in particular of the alpha4beta2-nAChR, which is obviously most severely reduced at the onset of AD, is a major contributor to the cognitive deterioration in AD. Accordingly, using 2-[18F]F-A85380 PET we showed significant declines in alpha4beta2-nAChRs in early AD-patients (Sabri et al. 2008; Kendziorra et al. 2010). However, this tracer was not well suited as a biomarker in a routine clinical set-up for early AD-diagnosis because of unfavourable properties (especially long acquisition times up to 7 hours). We, therefore, developed the new radiotracer (-)-[18F]NCFHEB (denominated as [18F]Flubatine) with significantly improved brain uptake and also better nAChR affinity and selectivity (Brust et al. 2008). Here, we present the results of the worldwide first ongoing [18F]Flubatine-PET study in humans.
Methods: 19 mild AD-patients (NINCDS-ADRDA, age 74.5±6.2, MMSE 23.7±2.7) and 20 age-matched healthy controls (HC, age 70.6±4.6, MMSE 28.5±0.8) underwent [18F]Flubatine-PET (370 MBq, 3D-acquisition, ECAT Exact HR+, 4 scans, 0-270 min p. i., motion correction with SPM2). All were nonsmokers and naïve for central acting medication. Kinetic modeling was applied to the VOI-based tissue-activity curves generated for 29 brain regions. Total distribution volume (DV) and binding potential (BP, reference region: corpus callosum) were used to characterize specific binding. Additionally, parametric images of DV were computed (Logan plot).
Results: Image quality of [18F]Flubatine scans was clearly superior to 2-[18F]F-A85380, and a 20 minutes scan already adequate for visual analysis. PET data acquired over only 90 minutes were sufficient to estimate all kinetic parameters of all VOIs with 1-tissue compartment model. Thirty-minute scans were already sufficient for modelling of all cortical VOIs. Tracer distribution was similar to known alpha4beta2-nAChR distribution and DVs in HCs increase as expected with receptor density with the lowest DV in the corpus callosum (5.64±0,87) and highest in the thalamus (24.67±3.91). The AD-patients showed significant BP reductions in distinct cortical regions (p<0.05) compared to HCs.
Conclusions: Due to significant faster kinetics and shorter acquisition time enabling full kinetic modeling within 90 minutes, and superior image quality [18F]Flubatine appears to be a much more suitable tracer than 2-[18F]F-A85380 to image alpha4beta2-nAChRs in humans. In keeping with its diagnostic properties, early AD-patients show declines of alpha4beta2-nAChRs in distinct cortical regions typically affected by AD-pathology. These results indicate that [18F]Flubatine-PET could have a great potential to be tested as a biomarker for early AD-diagnosis.