title: Design, synthesis and structure-activity relationship of rhenium 2-arylbenzothiazoles as β-amyloid plaque binding agents.
abstract: To continue our efforts toward the development of (99m)Tc PiB analogs, we have synthesized 24 neutral and lipophilic Re (as a surrogate of (99m)Tc) 2-arylbenzothiazoles, and explored their structure-activity relationship for binding to Aβ1-40 fibrils. These Re complexes were designed and synthesized via the integrated approach, so their (99m)Tc analogs would have a greater chance of crossing the blood-brain barrier. While the lipophilicities (logPC18=1.59-3.53) of these Re 2-arylbenzothiazoles were all within suitable range, their binding affinities (Ki=30-617nM) to Aβ1-40 fibrils varied widely depending on the selection and integration of the tetradentate chelator into the 2-phenylbenzothiazole pharmacophore. For potential clinical applications, further refinement to obtain Re 2-arylbenzothiazoles with better binding affinities (<10nM) will likely be needed. The integrated approach reported here to generate compact, neutral and lipophilic Re 2-arylbenzothiazoles could be applied to other potent pharmacophores as well to convert other current Aβ PET tracers to their (99m)Tc analogs for more widespread application via the use of SPECT scanners.
authors: Department of Molecular Oncology, BC Cancer Agency, Vancouver, BC, Canada V5Z1L3.
authors: Jinhe
authors: J
authors: Pan
authors: Neale S
authors: NS
authors: Mason
authors: Manik L
authors: ML
authors: Debnath
authors: Chester A
authors: CA
authors: Mathis
authors: William E
authors: WE
authors: Klunk
authors: Kuo-Shyan
authors: KS
authors: Lin
mesh_terms: D000544:Alzheimer Disease / Q000000981:diagnostic imaging; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D056831:Coordination Complexes / Q000138:chemical synthesis* / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D015609:Organotechnetium Compounds / Q000737:chemistry; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D011859:Radiography; D012211:Rhenium / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry* / Q000378:metabolism; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: D016229:Amyloid beta-Peptides; D056831:Coordination Complexes; D015609:Organotechnetium Compounds; D010446:Peptide Fragments; D013844:Thiazoles; C078592:amyloid beta-protein (1-40); D012211:Rhenium; C070845:2-phenylbenzothiazole