Preclinical Properties of 18 F-AV-45: A PET Agent for Aβ Plaques in the Brain

Tian

Proc. Natl. Acad. Sci. U.S.A.

et al. 2015

192

170

Near-infrared fluorescence (NIRF) molecular imaging has been widely applied to monitoring therapy of cancer and other diseases in preclinical studies; however, this technology has not been applied successfully to monitoring therapy for Alzheimer's disease (AD). Although several NIRF probes for detecting amyloid beta (Aβ) species of AD have been reported, none of these probes has been used to monitor changes of Aβs during therapy. In this article, we demonstrated that CRANAD-3, a curcumin analog, is capable of detecting both soluble and insoluble Aβ species. In vivo imaging showed that the NIRF signal of CRANAD-3 from 4-mo-old transgenic AD (APP/PS1) mice was 2.29-fold higher than that from age-matched wild-type mice, indicating that CRANAD-3 is capable of detecting early molecular pathology. To verify the feasibility of CRANAD-3 for monitoring therapy, we first used the fast Aβ-lowering drug LY2811376, a well-characterized beta-amyloid cleaving enzyme-1 inhibitor, to treat APP/PS1 mice. Imaging data suggested that CRANAD-3 could monitor the decrease in Aβs after drug treatment. To validate the imaging capacity of CRANAD-3 further, we used it to monitor the therapeutic effect of CRANAD-17, a curcumin analog for inhibition of Aβ cross-linking. The imaging data indicated that the fluorescence signal in the CRANAD-17-treated group was significantly lower than that in the control group, and the result correlated with ELISA analysis of brain extraction and Aβ plaque counting. It was the first time, to our knowledge, that NIRF was used to monitor AD therapy, and we believe that our imaging technology has the potential to have a high impact on AD drug development.Alzheimer's | amyloid | imaging | fluorescence | curcumin

Section: Discussionmentioning

confidence: 99%

“…Several NIRF probes for insoluble Aβs have been reported (37)(38)(39)(40)(41)(42)(43)(44)(45). It has been almost 10 y since the first report of NIRF imaging of Aβs by Hintersteiner et al in 2005 (41).…”

mentioning

confidence: 99%

Near-infrared fluorescence molecular imaging of amyloid beta species and monitoring therapy in animal models of Alzheimer’s disease

Tian

Proc. Natl. Acad. Sci. U.S.A.

et al. 2015

192

170

“…[3][4][5][6] Many radiolabeled probes for imaging β-amyloid based on Congo Red, thioflavin T, and DDNP have been reported. Among them, [ 11 C]PIB, 7,8 20,21 have been tested clinically and demonstrated potential utility.…”

mentioning

confidence: 99%

Novel Benzofurans with ^99mTc Complexes as Probes for Imaging Cerebral β-Amyloid Plaques

Ono

Fuchi

Fuchigami

et al. 2010

ACS Med. Chem. Lett.

Bioorganic & Medicinal Chemistry Letters

“…Many PET/SPECT probes for imaging -amyloid based on Congo Red, thioflavin T, and DDNP have been reported. Among them, [ 11 C]PIB 5,6, [ 11 C]SB-13 7,8 17,18 have been tested clinically and demonstrated potential utility.…”

mentioning

confidence: 99%

99mTc/Re complexes based on flavone and aurone as SPECT probes for imaging cerebral β-amyloid plaques

Ono

Ikeoka

Watanabe

et al. 2010

Two 99m Tc/Re complexes based on flavone and aurone were tested as potential probes for imaging -amyloid plaques using single photon emission computed tomography. Both 99m Tc-labeled derivatives showed higher affinity for A aggregates than did 99m Tc-BAT. In sections of brain tissue from an animal model of AD, the Re-flavone derivative 9 and Re-aurone derivative 19 intensely stained -amyloid plaques. In biodistribution experiments using normal mice, 99m Tc-labeled flavone and aurone displayed similar radioactivity pharmacokinetics. With additional modifications to improve their brain uptake, 99m Tc complexes based on the flavone or aurone scaffold may serve as probes for imaging cerebral -amyloid plaques Key words: Alzheimer's disease, -amyloid plaque, Tc-99m, single photon emission computed tomography (SPECT), imaging. Ono et al. 3/38Alzheimer's disease (AD) is a neurodegenerative disorder of the brain associated with irreversible cognititive decline, memory impairment, and behavioral changes.Currently, the only definitive confirmation of AD is by postmortem histopathological examination of -amyloid plaques in the brain. The early appraisal of clinical symptoms for a diagnosis of AD is often difficult and unreliable. Numerous reports suggest the accelerated accumulation of -amyloid plaques in the brain to be a key risk factor associated with AD. Consequently, the detection of individual -amyloid plaques in vivo by single photon emission tomography (SPECT) or positron emission tomography (PET) should improve the diagnosis of and also accelerate the discovery of effective therapeutic agents for AD [1][2][3][4] There are more SPECT scanners than PET imaging devices installed for routine clinical imaging, which provides a certain advantage to using SPECT imaging agents. Since SPECT is more valuable than PET in terms of routine diagnostic use, the development of more useful Aβ imaging agents for SPECT has been a critical issue. Although many radioiodinated SPECT imaging agents for detecting β-amyloid plaques have been reported, there are few reports on the development of 99m Tc imaging agents. Ono et al. 4/38 99m Tc (T 1/2 = 6.01 h, 141 keV) has become the most commonly used radionuclide in diagnostic nuclear medicine for several reasons: it is readily produced by an 99 Mo/ 99m Tc generator, the gamma-ray energy it emits is suitable for detection, and its physical half-life is compatible with the biological localization and residence time required for imaging. Its ready availability, essentially 24 h a day, and easiness of use make it the radionuclide of choice. New 99m Tc-labeled imaging agents will provide simple, convenient, and widespread SPECT-based imaging methods for detecting and eventually quantifying-amyloid plaques in living brain tissue.It has been reported that a dopamine transporter imaging agent, [ 99m Tc]TRODAT-1, is useful to detect the loss of dopamine neurons in the basal ganglia associated with Parkinson's disease. This is the first example of a 99m Tc imaging agent t...