I have come to the conclusion that PIB-Pet just can't see the early changes that happen when PBT2 is used to treat. The trial failed the drug not the other way around. Perhaps there are some other reads (blood chemistry, etc) that will elucidate the problem in the draft results.
A better biomarker might be this-
Synthesis and PET imaging studies of [18F]2-fluoroquinolin-8-ol([18F]CABS13) in transgenic mouse models of Alzheimer’s disease
Neil Vasdev, et., al., 2012
Benzyloxy-2-chloroquinoline was reacted with fluorine-18 labelled potassium cryptand fluoride, followed by catalytic hydrogenation to prepare [18F]2-fluoroquinolin-8-ol in high radiochemical yields (30%; uncorrected and relative to [18F]-fluoride), specific activities (>1 Ci mmol1) and radiochemical purities (>99%) within 70 min; PET-CT imaging with this new radiotracer in double transgenic mice shows excellent promise for imaging Alzheimer’s disease. From Intro Increased concentrations of Fe, Cu and Zn ions have been observed in amyloid plaques and are purported to impose Ab-pathogenicity,10 with levels of Fe and Zn ions reported with concentrations as high as 1 mM in the vicinity of amyloid plaques. Ionophores and metal-chelators have emerged as therapeutics to target these metal ions as part of the ‘‘metal hypothesis of Alzheimer’s disease’’, and have been the subject of several recent reviews. Promising clinical studies with the 8-hydroxyquinoline derivatives, clioquinol (CQ) and PBT2, as well as a PET imaging study with [18F]2-fluoro-2-deoxy-Dglucose ([18F]FDG) revealed that CQ may improve glucose metabolism and halt cognitive deterioration in subjects with familial AD. These efforts sparked the development of radioiodinated CQ derivatives for imaging patients suffering from AD. Although CQ and CQ showed low brain uptake in transgenic mouse models and human with single-photon mission computed tomography (SPECT) imaging studies, respectively, uptake of [125I]CQ was somewhat improved in mice by incorporation of the radiotracer into butylcyanoacrylate nanoparticles, though their preparation is cumbersome. The goal of the present work is to develop a PET radiotracer based on a hydroxyquinoline chelator and evaluate its potential for detecting amyloid plaques via imaging studies in transgenic rodent models.
3 Conclusions
Fluorine-18 labelled 1 and other quinoline-based imaging agents show excellent promise to improve the specificity of existing radiopharmaceuticals for imaging AD and related dementias. Further imaging studies and biological characterization of [18F]1 as an imaging agent for AD (and several other illnesses related to metallobiology), as well as optimization and automation of the radiosynthesis of [18F]-labelled fluoroquinolinol derivatives are currently underway in our laboratories.
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