Synthesis and evaluation of ¹¹C-labeled 6-substituted 2-arylbenzothiazoles as amyloid imaging agents

The synthesis and evaluation of a series of neutral analogues of thioflavin-T (termed BTA's) with high affinities for aggregated amyloid and a wide range of lipophilicities are reported. Radiolabeling with high specific activity [¹¹C]methyl iodide provided derivatives for in vivo evaluation. Brain entry in control mice and baboons was high for nearly all of the analogues at early times after injection, but the clearance rate of radioactivity from brain tissue varied by more than 1 order of magnitude. Upon the basis of its rapid clearance from normal mouse and baboon brain tissues, [N-methyl-¹¹C]2-(4′-methylaminophenyl)-6- hydroxybenzothiazole (or [¹¹C]6-OH-BTA-1) was selected as the lead compound for further evaluation. The radiolabeled metabolites of [¹¹C]6-OH-BTA-1 were polar and did not enter brain. The binding affinities of [N-methyl-³H]6-OH-BTA-1 for homogenates of postmortem AD frontal cortex and synthetic Aβ(1-40) fibrils were similar (K_d = 1.4 nM and 4.7 nM, respectively), but the ligand-to-Aβ peptide binding stoichiometry was ∼400-fold higher for AD brain than Aβ(1-40) fibrils. Staining of AD frontal cortex tissue sections with 6-OH-BTA-1 indicated the selective binding of the compound to amyloid plaques and cerebrovascular amyloid. The encouraging in vitro and in vivo properties of [¹¹C]6-OH-BTA-1 support the choice of this derivative for further evaluation in human subject studies of brain Aβ deposition.