Structure–Activity Relationships of Radioiodinated Benzoimidazopyridine Derivatives for Detection of Tau Pathology

Abstract

It is generally accepted that neurofibrillary tangles consisting of tau proteins are involved in the pathogenesis of Alzheimer's disease (AD). For selective detection of tau pathology, we synthesized and evaluated radioiodinated benzoimidazopyridine (BIP) derivatives with an alkylamino group as tau imaging probes. selectivity to tau aggregates and pharmacokinetics of BIP derivatives varied markedly, being strongly dependent on the alkylamino group. In autoradiography with AD brain sections, the BIP derivative with a dimethylamino group (BIP-NMe) showed the highest selectivity to tau aggregates. Regarding the biodistribution using normal mice, the BIP derivative with an ethylamino group (BIP-NHEt) showed the highest uptake (6.04% ID/g at 2 min postinjection) into and rapid washout (0.12% ID/g at 60 min postinjection) from the brain. These results suggest that the introduction of an optimal alkylamino group into the BIP scaffold may lead to the development of more potential tau imaging probes.

Characterization and Optimization of Benzimidazopyrimidine and Pyridoimidazopyridine Derivatives as Tau-SPECT Probes

“…17 In addition, these values were higher than those for [ 125 I]BIP-NMe 2 (3.98% ID/g and 10.5, respectively) and [ 125 I]BIP-NHEt (6.04% ID/g and 15.5, respectively). 14,15 These results suggest that [ 125 I]PIP-NHMe and [ 125 I]PIP-NHEt have promising brain pharmacokinetics as tau imaging probes.…”

“…First, an in vitro autoradiographic study with two different types of AD brain sections (Aβ­(+)/tau(−) and Aβ­(+)/tau­(+)) was carried out to evaluate the selective binding affinity to tau against Aβ aggregates according to the same method as reported in our previous studies (Figures and ). − As shown in Figure S1, Aβ aggregates were observed in the gray matter of both brain sections, whereas tau aggregates accumulated only in the gray matter of Aβ­(+)/tau­(+) brain sections. Accordingly, the radioactivity of ideal tau imaging probes should be specifically observed in the gray matter of Aβ­(+)/tau­(+) brain sections.…”

“…In our exploratory research for the development of novel tau imaging probes, we found that benzimidazopyridine (BIP), which is a fused nitrogen tricyclic scaffold, shows potential as a backbone for useful tau imaging probes for SPECT . Structure–affinity and brain kinetics relationship studies revealed that BIP derivatives with an alkylamino group showed favorable binding affinity for tau aggregates and brain pharmacokinetics in the murine brain. , Additionally, we recently reported that benzimidazopyrimidine (BIPM) and pyridoimidazopyridine (PIP), which are also categorized as fused nitrogen tricyclic scaffolds, are novel scaffolds for the development of tau imaging probes . The radioiodinated BIPM and PIP derivatives with a dimethylamino group ([ 125 I]­BIPM-NMe 2 and [ 125 I]­PIP-NMe 2 ) displayed selective in vitro binding affinity for tau against β-amyloid (Aβ) aggregates and favorable pharmacokinetics in the murine brain.…”

“…Useful tau imaging probes should show high initial uptake into (>4% ID/g at 2 min postinjection) and rapid clearance from (<1% ID/g at 30 min postinjection) the murine brain. , [ 125 I]­BIPM-NHMe and all of the PIP derivatives satisfied these criteria; especially, the brain uptakes at 2 min postinjection and the 2 min/30 min ratios for [ 125 I]­PIP-NHMe (6.62% ID/g and 38.9, respectively) and [ 125 I]­PIP-NHEt (6.86% ID/g and 28.6, respectively) were superior to those for [ 125 I]­PIP-NMe 2 (5.73% ID/g and 27.3, respectively) . In addition, these values were higher than those for [ 125 I]­BIP-NMe 2 (3.98% ID/g and 10.5, respectively) and [ 125 I]­BIP-NHEt (6.04% ID/g and 15.5, respectively). , These results suggest that [ 125 I]­PIP-NHMe and [ 125 I]­PIP-NHEt have promising brain pharmacokinetics as tau imaging probes.…”

“…14 Structure−affinity and brain kinetics relationship studies revealed that BIP derivatives with an alkylamino group showed favorable binding affinity for tau aggregates and brain pharmacokinetics in the murine brain. 15,16 Additionally, we recently reported that benzimidazopyrimidine (BIPM) and pyridoimidazopyridine (PIP), which are also categorized as fused nitrogen tricyclic scaffolds, are novel scaffolds for the development of tau imaging probes. 17 pharmacokinetics in the murine brain.…”