Development of a PET/SPECT agent for amyloid imaging in Alzheimer's disease.
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.
Department of Medicinal Chemistry and Pharmacology, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, USA. ymwang@uic.edu
Yanming
Y
Wang
William E
WE
Klunk
Manik L
ML
Debnath
Guo-Feng
GF
Huang
Daniel P
DP
Holt
Li
L
Shao
Chester A
CA
Mathis
D000368:Aged; D000544:Alzheimer Disease / Q000000981:diagnostic imaging* / Q000473:pathology / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000032:analysis*; D000814:Aniline Compounds / Q000138:chemical synthesis / Q000493:pharmacokinetics; D000818:Animals; D052160:Benzothiazoles; D001667:Binding, Competitive / Q000502:physiology; D001921:Brain / Q000000981:diagnostic imaging* / Q000473:pathology / Q000503:physiopathology; D002250:Carbon Radioisotopes; D002531:Cerebellum / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism; D006801:Humans; D007457:Iodine Radioisotopes; D008657:Metabolic Clearance Rate / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D015394:Molecular Structure; D058225:Plaque, Amyloid / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D049268:Positron-Emission Tomography / Q000379:methods; D011869:Radioligand Assay; D013844:Thiazoles / Q000138:chemical synthesis / Q000493:pharmacokinetics; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods
C494130:2-(3'-iodo-4'-methylaminophenyl)-6-hydroxybenzothiazole; D016229:Amyloid beta-Peptides; D000814:Aniline Compounds; D052160:Benzothiazoles; D002250:Carbon Radioisotopes; D007457:Iodine Radioisotopes; D013844:Thiazoles; C005465:benzothiazole