Probe development for systemic molecular imaging of Alzheimer’s disease

Ran C. Probe development for systemic molecular imaging of Alzheimer’s disease, in World Molecular Imaging Congress, 2016, Sept.11-14. New York ; Working Paper.Abstract

Molecule imaging is an indispensible tool for diagnosis, treatment and basic mechanism studies. For a specific disease, the majority of research has been focusing on a single-biomarker imaging, which is particularly important for the purpose of diagnosis. However, given the complex nature of most diseases, systemic molecular imaging (SYMI) of multiple biomarkers of a single disease can be crucial for understanding its mechanism, and for designing more efficient therapeutics.

Alzheimer’s disease (AD) is a multi-facet neurodegenative disease with multi-dimensional biomarkers. If the biomarkers of AD are considered in a multi-dimensional space, each category of biomarkers could be considered as one coordination axis. Amyloid beta (Ab) deposits and tau tangles are the most prominent pathological hallmarks of AD, and Ab and tau species respectively represent two essential axis of biomarkers of AD. It is also well accepted that oxidative stress is highly associated with AD, and reactive oxygen species (ROS) could also be considered as another important biomarker dimension of AD. Considering AD biomarkers in a three-dimensional (3D) space, Ab, tau and ROS could be considered as x, y, z-coordination axis correspondingly.

This presentation will focus on our recent results from our laboratory in systemic molecular imaging of AD, particularly on the biomarker dimensions of Aβs and ROS. On the axis of Aβ, multiple sub-species, including insoluble and soluble Aβs consist a complex family of biomarkers. Currently, it is not clear which sub-species could serve as a better biomarker for AD severity and progression. In the past few years, our research has been concentrated on three-phase development of “smart” NIRF probes for various Aβ species. In phase (I), we developed a new family of NIR fluorescent dyes (termed CRANAD-X) for insoluble Aβs. In phase (II), we have successfully developed NIRF probes for both soluble and insoluble Aβ species. In phase (III) we have concentrated our efforts on developing imaging probes that are selective for soluble Aβs. On the ROS axis, we have first designed NIRF probes for detection of H₂O₂, and then designed NIRF probes that are sensitive to various ROS. Our data showed the excellent correlation between ROS levels and the progression of AD. Taken together, with imaging probes for different dimensions of AD biomarkers, we believe that systemic molecular imaging will be a vital approach for understanding the complexity of AD, and for efficiently assisting AD drug development.

Reference

1. Ran C, Xu X, Raymond SB, Ferrara BJ, Neal K, Bacskai BJ, Medarova Z, Moore A, J. Amer. Chem. Soc., 2009,131(42):15257-61.
2. Zhang X, Tian Y, Li Z, Tian X, Sun H, Liu H, Moore A, Ran C.*, J. Amer. Chem. Soc., 2013, 135(44):16397-409.
3. Zhang X, Tian Y, Yuan P, Li Y., Yaseen MA, Grutzendler J, Moore A, Ran C.*, Chem. Commun., 2014, 50(78):11550-3.
4. Zhang X, Tian Y, Zhang C, Tian X, Ross AW, Moir RD, Sun H, Tanzi RE, Moore A, and Ran C*, Proc. Natl. Aca Sci. USA, 2015, 112(31):9734-9.

Oxalate-curcumin based probe for micro- and macro-imaging of reactive oxygen species in Alzheimer’s disease

et al Yang, J. RC. Oxalate-curcumin based probe for micro- and macro-imaging of reactive oxygen species in Alzheimer’s disease. Proc. Natl. Acad. Sci. USA. In Press.Read more

Tuning Stereo-hindrance of Curcumin Scaffold for Selective Imaging of Soluble Forms of Amyloid Beta Species

Li Y. Tuning Stereo-hindrance of Curcumin Scaffold for Selective Imaging of Soluble Forms of Amyloid Beta Species. Chem. Sci. In Press.Abstract

Amyloid peptides and proteins are associated with pathologies of numerous diseases. In the progression of a disease, amyloids exist in soluble and insoluble forms, which are dominated species at different stages of the disease and have different degree of toxicities. However, differentiating the soluble and insoluble forms is very challenging with small molecule probes, due to multiple layers of hurdles. Inspired by the recognition principle of antibodies for sAβ, we hypothesized that the accessibility/tightness of soluble and insoluble amyloids could be utilized to design imaging probes to recognize different amyloid forms, and stereo-hindrance tuning strategy could be used to design imaging probes for selectively detecting soluble amyloid beta (sAβ) species in Alzheimer’s disease (AD). Herein, we demonstrated that tuning the stereo-hindrance of phenoxy-alkyl chains at 4-position of curcumin scaffold could lead to certain selectivity for sAβ over insoluble Aβs (insAβ). Among the designed compounds, CRANAD-102 showed a 68-fold higher affinity to sAβ than insAβ (7.5±10 nM vs. 505.9±275.9 nM). Moreover, our imaging data indicated that CRANAD-102 was indeed capable of detecting sAβ in vivo using 4-months old APP/PS1 mice, in which sAb are the predominant species in the brains. In addition, we also demonstrted that CRANAD-102 could be used to monitor the increasing of sAβ loading from the ages of 4-months old to 12-months old. We believe that CRANAD-102 can be a useful probe for selectively detecting sAβ species in AD, and our probe designing strategy can be applied to other amyloids, and will have tremendous impact on AD drug development and other amyloid research.

PET imaging of human brown adipose tissue with TSPO tracer [¹¹C]PBR28

Ran C. PET imaging of human brown adipose tissue with TSPO tracer [¹¹C]PBR28. Molecular Imaging & Biology. In Press.Abstract

Purpose: Brown adipose tissue (BAT) in adult humans has been recently re-discovered and intensively investigated as a new potential therapeutic target for obesity and type 2 diabetes (T2D). However, reliable assessment of BAT mass in vivo represents a considerable challenge. The purpose of this study is to demonstrate for the first time that human BAT depots can be imaged with a TSPO-specific PET tracer [¹¹C]PBR28 under thermoneutral conditions.

Procedures: In this retrospective study, we analyzed the images of three healthy volunteers who underwent PET/MR imaging after injection of 14mCi of [¹¹C]PBR28 at room temperature. Thirty-minute static PET images were reconstructed from the data obtained 60-90 minutes after the injection of the tracer .

Results: [¹¹C]PBR28 uptake in the neck/supraclavicular regions was identified, which was parallel to the known distribution pattern of human BAT depots. These areas co-localized with the areas of hyperintensity and corresponded to fat on T1 weighted MR images. Standardized uptake value (SUV) was used to quantify [¹¹C]PBR28 signal in BAT depots. The average (± SD) SUV_(mean) and SUV_max for BAT depots was 2.13 (±0.33) and 3.19 (±0.34) respectively, while the average SUV_(mean)for muscle and subcutaneous adipose tissue was 0.79 (±0.1) and 0.18 (±0.04) respectively.

Conclusions: In this brief article, we provide the first evidence suggesting that [¹¹C]PBR28, a widely available TSPO-specific PET tracer, can be used for imaging human BAT mass under thermoneutral conditions.

Drug screening: Don't discount all curcumin trial data

Hege M, Frautschy S, Schubert D, Maher P, Ran C, Moore A, Bacskai BJ, Koronyo-Hamaoui M, Koronyo Y, Martins R, et al. Drug screening: Don't discount all curcumin trial data. Nature [Internet]. 2017;543 :40. Publisher's Version Read more

Synthesis-Free PET Imaging Of Brown Adipose Tissue And TSPO Via Combination Of Disulfiram And 64CuCl2

Yang J. Synthesis-Free PET Imaging Of Brown Adipose Tissue And TSPO Via Combination Of Disulfiram And 64CuCl2. Scientific Reports [Internet]. 2017;7 :8298. Publisher's Version Read more

Chongzhao Ran, PhD

Molecular Imaging and Therapeutics Development Lab

Curcumin based NIRF probes CRANAD-X

Topdown screening of NIRF imaging probes for brown adipose tissue (BAT)

Amyloid pathology and the 1st and 2nd generations of imaging probes

Double-blocking strategy for anti-crosslinking of amyloid beta species

The interaction model of curcumin analogues with amyloid beta peptides

NIRF imaging of AD mice with CRANAD-58

Two-photon imaging of AD mice with CRANAD-28

NIRF imaging with CRANAD-3 for monitoring therapeutic effects of BACE-1 inhibitor LY2811376 and CRANAD-17

Chemistry and spectral characterization of CRANAD-X

NIRF Imaging of brown adipose tissue (BAT) with CRANAD-29