Detection of amyloid plaques by radioligands for Aβ40 and Aβ42 -: Potential imaging agents in Alzheimer's patients

Alzheimer's disease (AD) is linked to increased brain deposition of amyloid-beta (Abeta) peptides in senile plaques (SPs), and recent therapeutic efforts have focused on inhibiting the production or enhancing the clearance of Abeta in brain. However, it has not been possible to measure the burden of SPs or assess the effect of potential therapies on brain Abeta levels in patients. Toward that end, we have developed a novel radioligand, [I-125]TZDM, which binds Abeta fibrils with high affinity, crosses the blood-brain barrier (BBB), and labels amyloid plaques in vivo. Compared to a styrylbenzene probe, [I-125]IMSB, [I-125]TZDM showed a 10-fold greater brain penetration and labeled plaques with higher sensitivity for in vivo imaging. However, this ligand also labels white matter, which contributes to undesirable high background regions of the brain. Interestingly, parallel to their differential binding characteristics onto fibrils composed of 40 (Abeta40)- or 42 (Abeta42)-amino-acid-long forms of Abeta peptides, these radioligands displayed differential labeling of SPs in AD brain sections under our experimental conditions. It was observed that [I-125]IMSB labeled SPs containing Abeta40, amyloid angiopathy (AA), and neurofibrillary tangles, whereas [I-125]TZDM detected only SPs and Abeta42-positive AA. Since increased production and deposition of Abeta42 relative to Abeta40 may be crucial for the generation of SPs, [I-125]TZDM and related derivatives may be more attractive probes for in vivo plaque labeling. Further structural modifications of TZDM to lower the background labeling will be needed to optimize the plaque-labeling property.