Radioiodinated styrylbenzenes and thioflavins as probes for amyloid aggregates.
We report for the first time that small molecule-based radiodiodinated ligands, showing selective binding to Abeta aggregates, cross the intact blood-brain barrier by simple diffusion. Four novel ligands showing preferential labeling of amyloid aggregates of Abeta(1-40) and Abeta(1-42) peptides, commonly associated with plaques in the brain of people with Alzheimer's disease (AD), were developed. Two 125I-labeled styrylbenzenes, (E,E)-1-iodo-2,5-bis(3-hydroxycarbonyl-4-hydroxy)styrylbenzene, 12 (ISB), and (E,E)-1-iodo-2,5-bis(3-hydroxycarbonyl-4-methoxy)styrylbenzene, 13 (IMSB), and two 125I-labeled thioflavins, 2-[4'-(dimethylamino)phenyl]-6-iodobenzothiazole, 18a (TZDM), and 2-[4'-(4''-methylpiperazin-1-yl)phenyl]-6-iodobenzothiazole, 18b (TZPI), were prepared at a high specific activity (2200 Ci/mmol). In vitro binding studies of these ligands showed excellent binding affinities with Kd values of 0.08, 0.13, 0.06, and 0.13 nM for aggregates of Abeta(1-40) and 0.15, 0.73, 0.14, and 0.15 nM for aggregates of Abeta(1-42), respectively. Interestingly, under a competitive-binding assaying condition, different binding sites on Abeta(1-40) and Abeta(1-42) aggregates, which are mutually exclusive, were observed for styrylbenzenes and thioflavins. Autoradiography studies of postmortem brain sections of a patient with Down's syndrome known to contain primarily Abeta(1-42) aggregates in the brain showed that both [(125)I]18a and [125I]18b labeled these brain sections, but [125I]13, selective for Abeta(1-40) aggregates, exhibited very low labeling of the comparable brain section. Biodistribution studies in normal mice after an iv injection showed that [125I]18a and [(125)I]18b exhibited excellent brain uptake and retention, the levels of which were much higher than those of [125I]12 and [125I]13. These findings strongly suggest that the new radioiodinated ligands, [125I]12 (ISB), [125I]13 (IMSB), [125I]18a (TZDM), and [125I]18b (TZPI), may be useful as biomarkers for studying Abeta(1-40) as well as Abeta(1-42) aggregates of amyloidogenesis in AD patients.
Zhuang
Z P
ZP
Departments of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Kung
M P
MP
Hou
C
C
Skovronsky
D M
DM
Gur
T L
TL
Plössl
K
K
Trojanowski
J Q
JQ
Lee
V M
VM
Kung
H F
HF
D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001345:Autoradiography; D001555:Benzene Derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism; D004314:Down Syndrome / Q000378:metabolism; D006801:Humans; D007202:Indicators and Reagents; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics; D007553:Isotope Labeling / Q000379:methods; D007700:Kinetics; D008024:Ligands; D051379:Mice; D010446:Peptide Fragments / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013343:Styrenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D014018:Tissue Distribution
D016229:Amyloid beta-Peptides; D001555:Benzene Derivatives; D007202:Indicators and Reagents; D007457:Iodine Radioisotopes; D008024:Ligands; D010446:Peptide Fragments; D013343:Styrenes; D013844:Thiazoles; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)