1. Development of New Generations of Imaging Probes for Amyloid beta Species.  My research has focused on the systematic development of imaging probes for diverse amyloid- (A) species through a three-phase strategy. This work was motivated by the recognition that distinct A species exhibit markedly different neurotoxicities: soluble oligomers are now widely regarded as the most neurotoxic forms, whereas insoluble plaques represent a later and comparatively less toxic stage of amyloid pathology. To address this complexity, we rationally designed the CRANAD-X series to span the full spectrum of amyloid pathology, from low-toxicity plaques to highly toxic soluble oligomers.

Phase I: Imaging insoluble A species. In the first phase, we focused on developing near-infrared fluorescence (NIRF) probes for insoluble A species, which are abundant misfolded proteins in the brains of patients with Alzheimers disease (AD). To enable noninvasive, longitudinal monitoring of amyloid pathology in AD mouse models, we invented a new family of NIRF dyes, termed CRANAD-X. These probes allow real-time visualization of insoluble A accumulation in vivo. Notably, we demonstrated that CRANAD-2 functions as a smart NIRF probe with high binding affinity for insoluble A and strong signal amplification (J. Am. Chem. Soc., 2009), establishing a powerful tool for preclinical AD research.

Phase II: Probes spanning soluble and insoluble A species. During the development of probes for insoluble A, accumulating evidence prompted a paradigm shift in the A hypothesis toward the critical role of soluble A species in AD pathogenesis. Although several PET tracers for insoluble A have received FDA approvaland a limited number of NIRF probes for insoluble A have been reportedno existing imaging probe was capable of capturing the full continuum of amyloidosis, from early soluble A accumulation to late-stage plaque deposition. In response, we developed CRANAD-3 and CRANAD-58, NIRF probes capable of detecting both soluble and insoluble A species. These probes have the potential to monitor the entire course of amyloid pathology during disease progression (J. Am. Chem. Soc., 2013; Proc. Natl. Acad. Sci. USA, 2015).

Phase III: Selective imaging of soluble A species for early detection. The earliest stage of amyloid pathology is characterized by excessive accumulation of A monomers and other soluble species, which gradually transitions to predominance of insoluble aggregates as AD progresses. For early molecular diagnosis, imaging probes that selectively target soluble A species are therefore highly desirable. In the third phase of this program, we focused on developing probes optimized for soluble A detection. By precisely tuning the steric hindrance of probe structures, we demonstrated that selective imaging of soluble A is achievable, exemplified by CRANAD-102 (Chem. Sci., 2017). This work provides a molecular basis for early detection of AD pathology.

Translation to PET imaging. In parallel, we developed a positron emission tomography (PET) tracer, ^18F-CRANAD-101, as a pan-A probe capable of detecting both soluble and insoluble A species. This tracer was designed to enhance sensitivity for early diagnosis and can be considered a lead compound for the development of next-generation A PET tracers.

a.     Ran C, Xu X, Raymond SB, Ferrara BJ, Neal K, Bacskai BJ, Medarova Z, Moore A, Design, synthesis, and testing of difluoroboron-derivatized curcumins as near-infrared probes for in vivo detection of amyloid-beta deposits. J. Amer. Chem. Soc., 2009,131(42):15257-61. PMCID: PMC278424.

b.     Zhang X, Tian Y, Li Z, Tian X, Sun H, Liu H, Moore A, Ran C.*, Design and Synthesis of Curcumin Analogues for in Vivo Fluorescence Imaging and Inhibiting Copper-Induced Cross-Linking of Amyloid Beta Species in Alzheimer's Disease, J. Amer. Chem. Soc., 2013, 135(44):16397-409. PMID: 24116384.

c.     Zhang X, Tian Y, Zhang C, Tian X, Ross AW, Moir RD, Sun H, Tanzi RE, Moore A, and Ran C*, Nearinfrared fluorescence molecular imaging of amyloid beta species and monitoring therapy in animal models of Alzheimer's disease, Proc. Natl. Acad. Sci. USA, 2015, 112(31):9734-9. PMID: 26199414.

d.     Li Y, Yang J, Liu H, Yang J, Du L, Feng H, Tian Y, Cao J, Ran C*, Tuning Stereo-hindrance of Curcumin Scaffold for Selective Imaging of Soluble Forms of Amyloid Beta Species, Chemical Science, 2017, 8: 7710-7717. PMID: 29568434.

2. Developing Highly Sensitive Chemiluminescence Probes for Misfolded Proteins. Although in vivo near-infrared fluorescence (NIRF) imaging with CRANAD-X probes shows considerable promise, its application is fundamentally constrained by shallow tissue penetration, primarily due to tissue autofluorescence and intrinsically low signal-to-noise ratios (SNR). As a result, achieving sufficient imaging depth in vivo remains a major challenge for fluorescence-based brain imaging. To overcome these limitations, we pioneered the development of chemiluminescence probes (ADLumin-X series) for deep-tissue imaging of misfolded proteins, including A species (Nature Commun., 2020). Leveraging the exceptionally high SNR and deep penetration afforded by ADLumin-5, we achieved the first in vivo three-dimensional whole-brain imaging using chemiluminescence probes, enabling precise spatial localization of A deposits throughout the brain. This 3D imaging capability represents a potential paradigm shift for molecular brain imaging in preclinical research (Proc. Natl. Acad. Sci. USA, 2023). Beyond A, we demonstrated that ADLumin-1 functions as a broadly applicable chemiluminescence probe capable of highly sensitive detection of multiple misfolded protein species both in vitro and in vivo (Research, 2025; Proc. Natl. Acad. Sci. USA, 2026). Furthermore, by integrating chemiluminescence resonance energy transfer (CRET) with dual, nonconjugated probes, we established a dual-amplification strategy that enables in vivo whole-brain imaging of both A and -synuclein with enhanced sensitivity (Nature Commun., 2020, and Proc. Natl. Acad. Sci. USA, 2026). Most recently, we demonstrated tissue penetration depths of up to 4 cm using chemiluminescence imaging, highlighting its potential for future clinical translation.

a.     Yang J, Yin W, Van R, Yin K, Wang P, Zheng C, Zhu B, Ran K, Zhang C, Kumar M, Shao Y, Ran C.*, Turn-on chemiluminescence probes and dual-amplification of signal for detection of amyloid beta species in vivo. Nature Commun. 2020, 11(1):4052. PMID: 32792510.

b.     Zhang J, Wickizer C, Ding W, Van R, Yang L, Zhu B, Yang J, Zhang C, Shen S, Shao Y, Ran C.*, In Vivo Three-dimensional Brain Imaging with Chemiluminescence Probes in Alzheimer's Disease Models. Proc. Natl. Acad. Sci. USA, 2023, 120(50): 2310131120. PMID: 38048460.

c.     Zhu B, Li Y, Kuang S, Wang H, Yu A, Zhang J, Yang J, Wang J, Shen S, Zhai X, Xie J, Ran C.*, Creating Chemiluminescence Signature Arrays Coupled with Machine Learning for Alzheimer's Disease Serum Diagnosis. Research, 2025, 8:0653. PMID: 40357359.

d.     Zhu B, Liu Z, Van R, Wang H, Kuang S, Jia Y, Leon EC, Yang F, Zhang J, Yang J, Hong H, Lobo F, Yu A, Wang J, Tanzi RE, Zhang C, Mao X, Shao Y, Ran C.*, Highly sensitive chemiluminescence imaging of misfolded proteins in neurodegenerative models. Proc. Natl. Acad. Sci. USA, 2026, 123(2):e2513311123. PMID: 41512036.

3. Molecularly Produced Light and Its Applications in Therapy and Imaging. Molecularly generated light, referred to here as molecular light, encompasses bioluminescence, chemiluminescence, and Cerenkov luminescence. A defining feature of molecular light is its dual identity as both a molecular entity and a light source. Because it is molecular in nature, molecular light can be delivered systemically and reach deep tissues throughout the body, thereby overcoming the fundamental limitations of externally applied light sources such as sunlight, lasers, and LEDs. At the same time, its intrinsic light-emitting properties enable diverse biomedical applications, including molecular imaging, photodynamic therapy, photo-oxidative therapy, and photobiomodulation (Angew. Chemie, 2023). We demonstrated that molecular light generated by the chemiluminescence probe ADLumin-4 is sufficient to replace externally applied LED illumination to initiate phototherapy in Alzheimers disease mouse models when combined with a photosensitizer, establishing a fully self-illuminated phototherapeutic paradigm in vivo (Angew. Chemie, 2023). Extending this concept, we showed that molecular light emitted from half-curcumin analogues can be used to image quasi-stable oxidized proteins in vivo and to perform sensitive in vitro liquid biopsy analyses using patient serum samples (Angew. Chemie, 2024). More recently, we discovered that the lophine derivative JIMI-11 produces molecular light via a molecular afterglow mechanism. We further demonstrated that this unique property can be leveraged to noninvasively monitor the therapeutic effects of the GLP-1 receptor agonist semaglutide in obese mouse models in vivo (Angew. Chemie, 2025).

a.     Ran C*, Pu K, Molecularly produced light and its biomedical applications. Angewandte Chemie, 2023, e202314468. PMID: 37955419.

b.     Kuang S, Zhu B, Zhang J, Yang F, Wu B, Ding W, Yang L, Shen S, Liang SH, Mondal P, Kumar M, Tanzi RE, Zhang C, Chao H, Ran C*, A Photolabile Curcumin-Diazirine Analogue Enables Phototherapy with Physically and Molecularly Produced Light for Alzheimer's Disease Treatment, Angewandte Chemie, 2023, 62(45):e202312519. PMID: 37721455.

c.     Yang J, Zhu B, Zhang J, Liang SH, Shen S, Ran C*. Half-Curcumin-Based Chemiluminescence Probes and Their Applications in Detecting Quasi-Stable Oxidized Proteins. Angewandte Chemie, 2024, 63(40):e202409896. PMID: 38980957.

d.     Yang J, Yang Y, Wang H, Liang SH, Ran C*., Molecular Afterglow of Lophine-Based Luminophore and Its Imaging Applications. Angewandte Chemie, 2025, e202507174. PMID: 40852797.

4. Development of Two-photon Imaging Probes. My laboratory has also pursued the development of multifunctional two-photon imaging probes for visualizing amyloid- (A) plaques and cerebral amyloid angiopathy (CAA). Using a rational molecular design strategy, we demonstrated that CRANAD-28, a highly bright bifunctional curcumin analogue, enables high-resolution two-photon imaging of A plaques and CAAs in vivo while simultaneously inhibiting A crosslinking, thereby combining diagnostic and modulatory functions within a single molecular scaffold (Chem. Commun., 2014). In parallel, we showed that PiB-C, a conjugate of Pittsburgh compound B (PiB) and a 12-crown-4 ether, readily penetrates the bloodbrain barrier and efficiently labels both A plaques and CAAs in APPPS1 transgenic mice when visualized by two-photon microscopy (Chem. Commun., 2014). These studies established two-photoncompatible probes as powerful tools for deep, high-resolution imaging of cerebral amyloid pathology. Beyond amyloid imaging, we developed CRANAD-61, a two-photon imaging probe capable of imaging reactive oxygen species (ROS) across both micro- and macroscopic scales using two-photon microscopy and in vivo molecular imaging, enabling dynamic visualization of oxidative stress in the living brain (Proc. Natl. Acad. Sci. USA, 2017). More recently, we designed fluorescence probes that can differentiate A40 and A42 within amyloid plaques, both in vitro and in vivo, using two-photon imaging, providing a molecular tool to interrogate plaque heterogeneity with isoform specificity (Chem. Sci., 2020).

a.     Zhang X, Tian Y, Yuan P, Li Y., Yaseen MA, Grutzendler J, Moore A, Ran C.*, A bifunctional curcumin analogue for two-photon imaging and inhibiting crosslinking of amyloid beta in Alzheimer's disease, Chem. Commun., 2014, 50(78):11550-3. PMID: 25134928.

b.     Tian Y, Zhang X, Li Y, Shoup T, Teng X, Elmaleh D, Moore A, Ran C.*, Crown ethers attenuate aggregation of amyloid beta of alzheimers disease. Chem. Commun. 2014, 50(99):15792-5. PMID: 25372154.

c.     Yang J, Zhang X, Yuan P, Yang J, Xu Y, Grutzendler J, Shao Y, Moore A, Ran C*, Oxalate-curcumin based probe for micro- and macro-imaging of reactive oxygen species in Alzheimers disease, Proc. Natl. Acad. Sci. USA, 2017, 114(47):12384-12389. PMID: 29109280.

d.     Yang J, Zhu B, Yin W, Han Z, Zheng C, Wang P, Ran C., Differentiating A40 and A42 in amyloid plaques with a small molecule fluorescence probe, Chem. Sci., 2020, 11, 5238-5245. PMID: 34122980.

5. Developing Imaging Probes and Methods for Diabetes and Obesity. My research also encompasses the development of molecular imaging probes and technologies for metabolically abnormal degeneration (MAD) diseases, including diabetes and obesity. Early in this effort, building on the molecular structure of streptozotocin (STZ)a small molecule with high specificity for pancreatic cellswe developed two -cellspecific near-infrared fluorescence (NIRF) probes, enabling noninvasive imaging of -cell populations (Angew. Chemie, 2007). My work also involved in brown adipose tissue (BAT), a re-emerging therapeutic and diagnostic target for MAD diseases such as diabetes and obesity. Despite its clinical importance, highly selective imaging probes for accurately quantifying BAT mass remain lacking. To address this unmet need, my primary contributions include: 1) the discovery of several NIRF probes suitable for imaging BAT mass using a top-down screening strategy (Sci. Rep. 2015); and 2) the demonstration that Cerenkov luminescence imaging (CLI), an emerging optical imaging modality, can be used to visualize BAT using 18F-FDG (Plos One, 2013). Compared with positron emission tomography (PET), CLI offers a significantly lower-cost and faster alternative for BAT imaging. In addition, we validated that TSPO is maker for BAT and TSPO PET tracer could be used for imaging BAT in mouse models and also in human subjects (Mol. Imag. Biol, 2019).

a.     Ran, C., Pantazopoulos, P., Medarova, Z., Moore, A., Synthesis and Testing of Beta-Cell-Specific Streptozotocin-Derived Near-Infrared Imaging Probes, Angew Chemie International Edition, 2007, 46(47), 8998-9001. PMID: 17957665.

b.     Zhang X, Kuo C, Moore A, Ran C*, In Vivo Optical Imaging of Interscapular Brown Adipose Tissue with 18F-FDG via Cerenkov Luminescence Imaging, PLOS One, 2013, 8(4):e62007. PMCID: PMC3634850.

c.     Zhang X, Tian Y, Zhang H, Kavishwar A, Lynes M, Brownell AL, Sun H, Tseng YH, Moore A, and Ran C^*, Curcumin analogues as selective fluorescence imaging probes for brown adipose tissue and monitoring browning, Scientific Reports, 2015, 5: 13116, doi:10.1038/srep13116.

d.     Ran C.*, Albrecht DS, Bredella MA, Yang J, Yang J, Liang SH, Cypess AM, Loggia ML, Atassi N, Moore A., PET Imaging of Human Brown Adipose Tissue with the TSPO Tracer [11C]PBR28. Mol Imaging Biol, 2018, 20(2):188-193. PMID: 28983743