In PET imaging study, [
18F]DRKXH1 is a small molecule and moderate lipophilic tracer. [
18F]DRKXH1 shows potential for ideal Aβ PET tracer, indicating that it can penetrate the complete blood–brain barrier and has high initial uptake in the frontal brain of mice[
12]. In AD transgenic mice, the brain uptake peaked at 6%ID/g. We observed that the initial brain uptake in AD transgenic mice was higher than that in WT mice. In addition, the bodyweight of AD transgenic mice was significantly higher than that of WT mice (46.63 ± 1.71 g vs. 23.04 ± 1.13 g,
t = 25.606,
P < 0.001), which is consistent with previous reports, wherein high initial brain uptake was detected in high-weight mice [
23]. Studies have showed that AD is related to BBB damage, which may lead to increased permeability [
24‐
26]. Therefore, we speculate that this phenomenon may be explained by BBB damage. Moreover, the presence of Aβ in AD transgenic mice, serving as the target site on [
18F]DRKXH1, may also cause the higher initial brain uptake in AD transgenic mice. Also, after the injection of [
18F]DRKXH1, AD transgenic mice had significantly higher DVR values than WT mice, indicating that [
18F]DRKXH1 has a high retention rate in the Aβ-rich brain regions and can locate Aβ plaques in the brain. The shallow non-specific binding provides high signal-to-noise images beneficial to the diagnosis of AD and efficacy evaluation of therapies targeting Aβ. Intriguingly, rodents are susceptible to the defluorination of many [
18F] labeled radioactive tracers, leading to a gradual increase in radioactivity in the skeleton [
22,
27]. The radioactive spillover from the skull introduced considerable error into the brain regions, as quantified by PET scans [
28]. Also, we observed a mild increase in bone radioactivity 0–5 min after injection, which was subsequently stable without apparent detachment during 5–60 min (0.97–1.1% ID/g). [
18F]-AV45 is an Aβ imaging agent approved by the FDA. Similar to [
18F]-AV45, [
18F]-DRKXH1 exhibits uptake that closely mirrored Aβ deposition in the brain, with higher DVR values than [
18F]-AV45. However, the difference in the autoradiography of human brain sections proposed that [
18F]DRKXH1 can distinguish between AD patients and healthy controls. Thus, this study verified the binding ability of [
18F]DRKXH1 to Aβ, but the experimental verification of the binding power of toxic amyloid oligomers is yet lacking. Next, we plan to perform PET imaging on transgenic mice for longitudinal studies using brain homogenates from these mice of different ages, Aβ fibers in human brain homogenates, and synthetic human Aβ fibers. The binding affinity assay verified the binding ability of DRKXH1 to Aβ oligomers. The results of preclinical experiments showed that [
18F]DRKXH1 has a high binding affinity and excellent imaging potential for Aβ in the brain of AD transgenic mice, low non-specific binding, and is rapidly eluted from the healthy brain.