Structure-Activity Relationship Study of Heterocyclic Phenylethenyl and Pyridinylethenyl Derivatives as Tau-Imaging Agents That Selectively Detect Neurofibrillary Tangles in Alzheimer's Disease Brains.
In order to explore novel tau-imaging agents that can selectively detect neurofibrillary tangles in Alzheimer's disease (AD) brains, we designed and synthesized a series of heterocyclic phenylethenyl and (3-pyridinyl)ethenyl derivatives with or without a dimethyl amino group. In in vitro autoradiography using AD brain sections, all radioiodinated ligands with a dimethyl amino group bound to Aβ deposits in the sections. In contrast, the ligands without a dimethyl amino group showed different patterns of radioactivity accumulation in the sections depending on the kind of heterocycle contained in their molecules. Particularly, a phenylethenyl benzimidazole derivative ([(125)I]64) showed marked radioactivity accumulation in the temporal lobe which corresponded with the distribution of tau deposits. [(125)I]64 also showed the most favorable pharmacokinetics in normal mouse brains (3.69 and 0.06% ID/g at 2 and 60 min postinjection, respectively) among all ligands in this study. Taken together, these results suggest that [(123)I]64 may be a new candidate tau-imaging agent.
Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University , 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
Kenji
K
Matsumura
Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University , 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
Masahiro
M
Ono
Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University , 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
Ayane
A
Kitada
Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University , 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
Hiroyuki
H
Watanabe
Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University , 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
Masashi
M
Yoshimura
Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University , 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
Shimpei
S
Iikuni
Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University , 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
Hiroyuki
H
Kimura
Department of Pathology, National Cerebral and Cardiovascular Center , 5-7-1 Fujishiro-dai, Suita, Osaka 565-8565, Japan.
Yoko
Y
Okamoto
Department of Stroke and Cerebrovascular Diseases, National Cerebral and Cardiovascular Center , 5-7-1 Fujishiro-dai, Suita, Osaka 565-8565, Japan.
Masafumi
M
Ihara
Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University , 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
Hideo
H
Saji
D000368:Aged; D000544:Alzheimer Disease / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001345:Autoradiography; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D001572:Benzofurans / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D052160:Benzothiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D001583:Benzoxazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007457:Iodine Radioisotopes; D008297:Male; D051379:Mice; D016874:Neurofibrillary Tangles / Q000000981:diagnostic imaging* / Q000378:metabolism; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013343:Styrenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D013702:Temporal Lobe / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D016875:tau Proteins / Q000378:metabolism*
C000603794:6-iodo-2-styryl-1H-benzo(d)imidazole; D016229:Amyloid beta-Peptides; D001562:Benzimidazoles; D001572:Benzofurans; D052160:Benzothiazoles; D001583:Benzoxazoles; D007457:Iodine Radioisotopes; D011725:Pyridines; D019275:Radiopharmaceuticals; D013343:Styrenes; D013876:Thiophenes; D016875:tau Proteins