P1‐125: PRECLINICAL AND CLINICAL CHARACTERIZATION OF 18F‐PM‐PBB3, A PET LIGAND FOR DIVERSE TAU PATHOLOGIES
Hitoshi Shimada, Maiko Ono, Kenji Tagai, Manabu Kubota, Soichiro Kitamura, Hiroyuki Takuwa, Chie Seki, Yasuyuki Kimura, Masanori Ichise, Hitoshi Shinotoh, Keisuke Takahata, Naoyoshi Yamamoto, Yasunori Sano, Yuhei Takado, Paul A. Tempest, Ming‐Kuei Jang, John Peter Seibyl, Olivier Barret, David Alagille, KENNETH L. MAREK · Alzheimer s & Dementia · 2018
C-pyridinylbutadienyl-benzothiazole 3 (C-PBB3), a tau PET ligand, can visualize tau pathologies in Alzheimer's disease (AD), non-AD tauopathies and tau transgenic mice. We have developed a F-labeled PBB3 derivative, F-PM-PBB3, to improve imaging characteristics of C-PBB3 and wider availability. The aims of the present study are to evaluate the potential utility of this ligand in AD and non-AD tauopathies, and to establish a simplified method for quantifying tau deposits by PET with F-PM-PBB3. To characterize the binding property of F-PM-PBB3 to diverse tau inclusions, we performed preclinical evaluations of F-PM-PBB3 using brain samples of humans and model mice. Furthermore, to perform a head-to-head comparison between F-PM-PBB3 and C-PBB3, patients with AD and non-AD tauopathies including progressive supranuclear palsy (PSP) and cognitively healthy subjects underwent PET scans with F-PM-PBB3 and C-PBB3. To evaluate the validity of the PET quantification of F-PM-PBB3 binding to tau pathology, arterial blood sampling was performed to determine the binding potential (BPND) of the radioligand based on a compartmental model. BPND by a reference tissue model and standardized uptake value ratio (SUVR) using cerebellum gray matter as a reference were also calculated. These estimates were compared to the SUVR value of C-PBB3 in each subject. Preclinical characterization revealed that F-PM-PBB3 can bind diverse tau pathologies, including AD, PSP, corticobasal degeneration, and Pick's disease, with high sensitivity and specificity. It was also demonstrated that F-PM-PBB3 cross-reacts with neither monoamine oxidase (MAO)-A nor MAO-B. In the clinical PET study, BPND value of F-PM-PBB3 calculated by a compartmental model was in good agreement with BPND determined by a reference tissue model as well as SUVR minus 1. F-PM-PBB3 yielded approximately 2-fold higher dynamic ranges of tau- specific signals than C-PBB3, while the distributions of specifically bound F-PM-PBB3 and C-PBB3 were in general agreement. F-PM-PBB3 did not produce prominent off-target signals in the basal ganglia. F-PM-PBB3 is a promising PET ligand for quantifying tau pathologies in AD and non-AD tauopathy patients with suitable pharmacokinetics, high contrast and minimal parenchymal off-target binding. SUVR can be used as a robust and simplified estimate of the specific radioligand binding.