Development of a PET/SPECT Agent for Amyloid Imaging in Alzheimer's Disease

Abstract

In the search for a cure for Alzheimer's disease (AD), efforts have been focused on preventing or reversing amyloid deposition in the brain. Efficacy evaluation of these antiamyloid therapies would greatly benefit from development of a tool for the in vivo detection and quantitation of amyloid deposits in the brain. Toward this goal, we have developed a series of benzothiazole derivatives as amyloid-imaging agents for positron emission tomography (PET). To extend the potential of these amyloid-imaging agents for routine clinical studies, we also set out to develop iodinated benzothiazole derivatives that could be used as dual agents for either PET or the complementary single photon emission computed tomography (SPECT). Such dual agents would permit PET or SPECT studies using radiotracers with the same chemical identity but labeled with different radionuclides. This would facilitate the validation of clinical SPECT studies, based on quantitative PET studies. In this work we report the synthesis and biological evaluation of a potent, selective, and brain-permeable benzothiazole compound, 2-(3'-iodo-4'-methylaminophenyl)-6-hydroxy-benzothialzole, termed 6-OH-BTA-1-3'-I (4), which can be radiolabeled with either positron-emitting carbon-11 or single photon-emitting iodine-125/iodine-123. The synthesis and radiolabeling of [125I]4 or [11C]4 were achieved through direct iodination with sodium [125I]iodide in the presence of chloramine T or through radiomethylation with [11C]CH3I. In vitro amyloid binding assays indicated that [125I]4 bound to amyloid deposits in a saturable manner and exhibited affinities in the nanomolar concentration range. Binding studies of [125I]4 to postmortem human brain homogenates also showed preference of binding to frontal cortex in the AD homogenates relative to age-matched control homogenates or cerebellum from either AD or control. In vivo pharmacokinetic studies in normal mice following iv injection of [11C]4 indicated that the radioligand entered the brain readily at early time points and cleared from the brain rapidly at later time points with a 2- to 30-min ratio >3. These results suggest that the new radioiodinated benzothiazole ligand might be useful as a surrogate marker for the in vivo quantitation of amyloid deposition in human brain for use with either PET or SPECT.

AD brain pathology: Vascular origins?

“…However, these findings do not reflect the possible interaction that takes place on a very local level. New possibilities to image cerebral amyloid deposits will permit longitudinal study of this question [7]. Further additional micro-analytic studies, such as those reporting co-localization of microbleeds, NFT and NP [2] are needed.…”

Impact of Beta-Amyloid-Specific Florbetaben PET Imaging on Confidence in Early Diagnosis of Alzheimer’s Disease

“…The Pittsburgh compound B (PIB), an analog of thioflavin T, represents the most widely used tracer for investigational PET imaging of beta-amyloid plaques in the brain. Retention of the 11C-labeled PiB ([C-11]PiB) has been shown to be approximately 2-fold greater in cortical areas of AD subjects relative to healthy controls, and the patterns of retention reflect the patterns of beta-amyloid deposition known from postmortem studies [15]. Florbetaben, an 18F-labeled tracer utilizing a radioisotope with a longer half-life than PIB [16,17] is currently being tested in a phase III clinical trial program.…”

Congo Red Staining of Amyloid: Improvements and Practical Guide for a More Precise Diagnosis of Amyloid and the Different Amyloidoses

“…Finally, there exists an intensive effort to diagnose the cerebral Aβ amyloid in Alzheimer's disease and congophilic amyloid angiopathy before the "point of no return" of the dementia has been reached, to try to arrest or even prevent this inexorably progressive disease. This effort is still in its early stage as exemplifi ed by some citations including the application of CR and thiofl avin analogues, and other substances (Klunk et al, 2001(Klunk et al, , 2003aBacskai et al, 2002Bacskai et al, , 2003Wiesehan et al, 2003;Wang et al, 2004).…”