99mTc-Labeled 2-Arylbenzothiazoles: Aβ Imaging Probes with Favorable Brain Pharmacokinetics for Single-Photon Emission Computed Tomography

A series of 2-arylbenzothiazole derivatives conjugated with bis(aminoethanethiol) (BAT) chelating groups were designed and synthesized. A competitive binding assay-based screening was used to select seven rhenium complexes with potent binding affinity toward A beta(1-42) aggregates (K-i < 50 nM) for Tc-99m labeling and further evaluation. The Tc-99m-labeled probes showed good affinity and specificity to A beta plaques in Tg mouse brain tissue in in vitro autoradiography studies. Moreover, [Tc-99m]14b exhibited favorable brain pharmacokinetics in normal mice (2.11% ID/g at 2 min and 0.62% ID/g at 60 min). Ex vivo autoradiography revealed extensive labeling of A beta plaques by [Tc-99m]14b in the brain of Tg mice. Furthermore, we performed the first single-photon emission computed tomography (SPECT) imaging study in nonhuman primates with Tc-99m-labeled A beta probes. The semiquantitative data showed that [Tc-99m]14b penetrated the brains of rhesus monkeys. These results indicate that [Tc-99m]14b could be utilized as a SPECT imaging probe for A beta plaques.