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. In vitro selectivity to tau aggregates and in vivo pharmacokinetics of BIP derivatives varied markedly, being strongly dependent on the alkylamino group. In in vitro autoradiography with AD brain sections, the BIP derivative with a dimethylamino group (BIP-NMe₂) 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.

Figure 1

¹²⁵I-labeled BIP derivatives reported as tau imaging probes.

Scheme 1

Reagent and conditions: (a) Boc₂O, DMAP, Et₃N, THF, 80 °C; (b) 2,5-dibromoaniline, CuI(I), 1,10-phenanthroline, Cs₂CO₃, xylene, 120 °C; (c) (SnBu₃)₂, Pd(PPh₃)₄, Et₃N, dioxane, 95 °C; (d) I₂, CHCl₃, rt; (e) TFA, CH₂Cl₂, rt; (f) CH₃I, NaH, 0 °C; (g) CH₃CH₂I, NaH, 0 °C; (h) CH₃CH₂CH₂I, NaH, 0 °C.

Scheme 2

Reagent and conditions: (a) (1) [¹²⁵I]NaI, H₂O₂, 1 N HCl, rt; (2) TFA, CHCl₃; (b) [¹²⁵I]NaI, H₂O₂, 1 N HCl, rt.

Figure 2

Comparison of in vitro autoradiograms with ¹²⁵I-labeled BIP derivatives in AD brain sections from the frontal (A) and temporal (B) lobes.

Figure 3

Quantitative analysis of in vitro autoradiography with AD brain sections. Data are presented as the mean ± SEM (n = 3–4).

Figure 4

Comparison of uptake into and clearance from the brain after the intravenous injection of ¹²⁵I-labeled BIP derivatives into normal mice (n = 5). ^aData were reported previously.