Synthesis, characterization, and preclinical validation of a PET radiopharmaceutical for interrogating Aβ (β-amyloid) plaques in Alzheimer’s disease

Guruswami S.M. Sundaram, Dhruva Dhavale, Julie L. Prior, Jothilingam Sivapackiam, Richard Laforest, Paul Kotzbauer, Vijay Sharma

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Background: PET radiopharmaceuticals capable of imaging β-amyloid (Aβ) plaque burden in the brain could offer highly valuable diagnostic tools for clinical studies of Alzheimer’s disease. To further supplement existing armamentarium of FDA-approved agents as well as those under development, and to correlate multiphoton-imaging data reported earlier, herein, we describe preclinical validation of a PET tracer. Methods: A novel PET radiopharmaceutical (18F-7B) was synthesized and characterized. To assess its affinity for Aβ, binding assays with Aβ1-42 fibrils, Alzheimer’s disease (AD) homogenates, and autoradiography studies and their IHC correlations were performed. For assessing its overall pharmacokinetic profiles in general and its ability to cross the blood-brain barrier (BBB) in particular, biodistribution studies in normal mice were performed. Finally, for evaluating potential for 18F-7B to serve as a targeted Aβ probe, the microPET/CT imaging was performed in age-matched amyloid precursor protein/presenilin-1 (APP/PS1) mice and wild-type (WT) counterparts. Results: The radiotracer 18F-7B shows saturable binding to autopsy-confirmed AD homogenates (Kd = 17.7 nM) and Aβ1-42 fibrils (Kd = 61 nM). Preliminary autoradiography studies show binding of 18F-7B to cortical Aβ plaques in autopsy-confirmed AD tissue sections, inhibition of that binding by unlabeled counterpart 7A-indicating specificity, and a good correlation of tracer binding with Aβ immunostaining. The agent indicates high initial penetration into brains (7.23 ± 0.47%ID/g; 5 min) of normal mice, thus indicating a 5-min/120-min brain uptake clearance ratio of 4.7, a benchmark value (>4) consistent with the ability of agents to traverse the BBB to enable PET brain imaging. Additionally, 18F-7B demonstrates the presence of parental species in human serum. Preliminary microPET/CT imaging demonstrates significantly higher retention of 18F-7B in brains of transgenic mice compared with their WT counterparts, consistent with expected binding of the radiotracer to Aβ plaques, present in APP/PS1 mice, compared with their age-matched WT counterparts lacking those Aβ aggregates. Conclusions: These data offer a platform scaffold conducive to further optimization for developing new PET tracers to study Aβ pathophysiology in vitro and in vivo.

Original languageEnglish
Article number33
JournalEJNMMI Research
Volume5
Issue number1
DOIs
StatePublished - Dec 27 2015

Keywords

  • Alzheimer’s disease
  • PET imaging
  • Radiopharmaceuticals
  • β-amyloid (Aβ)

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