JMC cover｜Shanghai Institute of Medical Research Molecular Imaging Center develops a small molecule near-infrared two-zone fluorescent osteoporosis diagnostic reagent based on azide bone targeting

Our country is gradually entering an aging society
.
It is predicted that by 2050, China’s elderly population will be close to 380 million, accounting for 27.
9% of the total population.
About one in three people will be an elderly person
.
Osteoporosis is a common disease that seriously threatens the physical and mental health of the elderly.
It is characterized by the reduction of bone mass per unit volume and the destruction of bone microstructure
.
The disease has a high incidence and more serious complications.
The most common and usually the most harmful complication is fractures, which restricts patients' activities and cannot take care of themselves, increases the incidence of lung infections and bedsores, which not only seriously affects The quality of life of patients and the increase in mortality also bring heavy economic burdens to individuals, families and society
.
Therefore, early and accurate diagnosis and long-term effective monitoring of osteoporosis are of great significance for preventing fractures and other related complications
.

The Old Man and Death, Joseph Wright of Derby (1734–1797)

Commonly used clinical imaging techniques for bone diseases include X-ray, CT, MRI, SPECT/CT and PET/CT
.
These imaging methods cannot achieve long-term rapid monitoring of osteoporosis due to the disadvantages of potential ionizing radiation hazards, high price, and low spatial and temporal resolution (Figure 1)
.
Optical imaging is a research hotspot in the field of biomedical imaging due to its characteristics of non-radiation, non-invasiveness, simple operation and low cost
.
Optical imaging is classified according to different wavelengths, 400-700 nm is visible and near-infrared one-zone imaging, and 1000-1700 nm is near-infrared two-zone imaging
.
Compared with near-infrared one-zone imaging, near-infrared two-zone fluorescence imaging has the advantages of deeper penetration (several centimeters), low background (less autofluorescence and scattering of biological tissues) and high detection sensitivity.
It is more suitable for optical imaging monitoring of osteoporosis.

.

Figure 1.
Several imaging techniques commonly used in the diagnosis of bone-related diseases and their respective advantages and disadvantages
.

　　On August 3, 2021, Cheng Zhen's team from the Molecular Imaging Center of Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chen Hao's team collaborated and published the title "Azide-Dye Unexpected Bone Targeting for Near-Infrared Window II Osteoporosis" in the Journal of Medicinal Chemistry .
The latest research results of "Imaging" report the use of small molecule fluorescent probes to conduct osteoporosis imaging studies in the near-infrared zone
.
The study was inspired by the significant difference in the pharmacokinetics of the anti-HIV drug zidovudine and the structurally similar drug stavudine.
The unique azide group of zidovudine was selected as the possible bone-targeting group and designed A bone-targeting probe that is different from traditional phosphonic acid modification has achieved good imaging results
.
The article was selected as the supplementary cover page introduction of the current magazine
.

　　Previously, the bone-targeting fluorescent probes that have been reported mostly use phosphonic acid to modify the bone-targeting group, which are mainly divided into two categories: one is the cyanine dye, which is mainly used in the near-infrared imaging window.
Shortcomings such as insufficient depth; another type of probe is nanomaterials, although it can image in the second zone window, but because it is composed of materials, there are shortcomings such as unknown long-term toxicity, which limits clinical conversion
.
Therefore, the development of water-soluble near-infrared two-zone bone targeting probe is of great significance
.

　　Azide is a common chemical group that can be transformed into various functional compounds and is widely used in biomedical research
.
However, so far few studies have reported the effect of azide on the pharmacokinetics of compounds in vivo
.
In this study, the researchers found an interesting phenomenon in the process of consulting the literature: two drugs for the treatment of AIDS, stavudine (d4T) and zidovudine (AZT), are nuclear structures with very similar structures.
Glycolic acid analog drugs (Figure 2)
.
Among them, zidovudine has a well-known myelosuppressive toxicity, and ¹⁴ C-labeled zidovudine pharmacokinetic studies have also confirmed that it accumulates in bone tissues in large quantities, with similar structure but no azide group Stavudine However, it did not show bone-related toxicity
.

Figure 2 Comparison of the structure and bone inhibitory side effects of deoxythymidine, stavudine and zidovudine

　　Based on this, the researchers designed and synthesized a water-soluble near-infrared two-region small molecule probe N ₃ -FEP-4T with an azide group and FEP-4T with a similar structure but no azide group as a control (such as Figure 3)
.
Preliminary research on the possible bone targeting effect of azide group
.

　　Figure 3 Structure comparison of water-soluble near-infrared two-zone small molecule probe N ₃ -FEP-4T and FEP-4T

　　After a series of in vitro experiments, the researchers used two probes to perform near-infrared two-zone fluorescence imaging of small animals in vivo.
Figure 4 below shows the comparison of the two when imaging normal mice in the prone position
.
As can be seen in the figure, the spine is clearly visible in the mouse imaged by N ₃ -FEP-4T, while the spine of the mouse imaged by FEP-4T is more blurred, suggesting that the azide group may help to achieve bone targeting
.

Figure 4 Comparison of bone imaging effects of N ₃ -FEP-4T and FEP-4T in normal mice

　　Next, the researchers used the N3-FEP-4T probe to perform diagnostic imaging in osteoporotic mice, and obtained good live and in vitro imaging results (Figure 5)
.
N ₃ -FEP-4T opens a new window for the biological application of azide-modified compounds, and provides an alternative design strategy for in vivo bone targeting besides classical phosphonic acid modification
.

Figure 5 Comparison of bone imaging effects of N ₃ -FEP-4T in normal mice and osteoporosis model mice

　　The Chen Hao research group of Shanghai Institute of Materia Medica and the Department of Nuclear Medicine of Huashan Hospital of Fudan University jointly trained postgraduate Zhang Xiaoqing, and Ji Aiyan, a staff member of Chen Hao's research group, are the co-first authors of this study
.
Researcher Cheng Zhen, researcher Chen Hao, and assistant researcher Qu Chunrong from the Molecular Imaging Center of Shanghai Institute of Materia Medica, and Professor Liu Xingdang from the Department of Nuclear Medicine, Huashan Hospital of Fudan University are the corresponding authors
.
The research was funded by the National Natural Science Foundation of China, Shanghai Pujiang Talents, and Shanghai Science and Technology Major Projects
.

　　Full text link: https://pubs.
acs.
org/doi/abs/10.
1021/acs.
jmedchem.
1c00839

　　(Contributor: Chen Hao's research group; Contributor: Zhang Xiaoqing)