English

• 0.   Introduction

  Health and disease are inevitable issues in the long history of human beings, and they have become themes to haunt human life. With the development of science and technology, some diseases have been controlled. The relationship between health and disease is shown in Fig.1^[1]. However, the cancer still threatens the health of human beings. The early diagnosis of tumours plays a significant role in the survival rate of patients. As an important part of medicine, the technique of molecular imaging plays a prominent role in the early detection and treatment of cancer^[2-3]. Molecular imaging relies on probes to qualitatively and quantitatively detect tumours. Recently, it can be detected as early as possible (even at the single-cell level), through imaging tools and probe molecules^[4-6].

  Figure 1

  

  Figure 1.  Close relationship between health and disease, lifestyle, and disease management^[1]

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  Molecular imaging includes ultrasound imaging (UI), computerized tomography (CT), magnetic resonance imaging (MRI), nuclear medical imaging (NMI), optical imaging (OI), and photoacoustic imaging (PI), et al^[7-10]. It should be specially explained that UI, CT, and MRI are considered molecular imaging techniques, while they are typically used to provide anatomical information. NMI is also known as radionuclide imaging, which mainly includes PET imaging and single-photon emission computed tomography (SPECT) imaging. It is well-known that the PET is the most advanced imaging tool with the highest sensitivity and accuracy. PET is a powerful tool with a noninvasive imaging modality for pre-examining fundamental biological processes in living subjects^[11-15]. The detection signal comes from radiation emission by the decay of a radionuclide. Only a picomolar level dose of tracer is employed for imaging. The imaging signal reflects the range and concentration distribution of the radioactive nuclide in the living body, and displays morphological and functional information of tissues and organs. It can detect physiological processes, which may not be apparent by routine staging procedures, and it can give quantitative information, resulting in revolutionary diagnostics and therapeutic monitoring in the clinic.

  In recent years, a large number of PET probe-based chemical materials have been reported. It is necessary to summarize the PET probe and design novel and efficient PET probes. Because of that, an overview of the PET probe is born. In the part of introduction, the technique of molecular imaging is discussed. Then, the conception of PET, the mechanism for PET imaging, and common radionuclides, especially the radioactive ¹⁸F, are introduced, as well as the simple presentation of SPECT. It highlights the various ¹⁸F-labelled PET probes in detail, and multi-modality probes. Meanwhile, the approaches for the fabrication of the ¹⁸F probe are proposed. It tends to cover wide fields. It can also provide many insights for the diagnosis and treatment of cancer. Finally, the challenge and prospect for the PET imaging probe are discussed.

  1.   Radionuclide of PET

  1.1   Positrons of PET

  Radionuclide decay through the emission of α, β, and γ rays. Radionuclide of PET emits a positron. A positron is similar to an electron with a positive charge, a certain mass, and energy. When it decays, a proton is converted into a neutron, while releasing a positron (β⁺) and a neutrino (ν). Thus, the atomic number (Z) is reduced, but the mass number (A) remains the original^[16-17]. The equation is as follows:

  ${ }_Z^A \mathrm{X} \rightarrow{ }_{Z-1}^{~~~~~A} \mathrm{Y}+\mathsf{β}^{+}+\nu+Q $

  X represents an element symbol. Y is the element after decay. Q is the decay energy. The positron nuclide undergoes β decay. As time goes on, the continuous decrease in the number of atoms during the decay obeys the exponential law and geometric series. As it decays, the number of lost atoms per unit of time is called radioactivity. Generally, the unit of radioactivity is Curie (Ci), representing decay of 3.7×10¹⁰ times per second. The international unit of radioactive activity is the Becquerel.

  1.2   Mechanism of radionuclide for PET imaging

  With the movement of a certain distance of positrons emitted by the nuclide, when their energy is exhausted, meet the negative electrons, and the positive and negative charges neutralize. According to equation of Einstein (E=mc²), the mass of positive and negative electrons is completely converted into energy of electromagnetic radiation. In the equation of Einstein, E represents energy, m stands for mass, and c is the speed of light in a vacuum. A pair of γ photons at an angle of 180° with the energy of 511 keV appeared, and they disappeared by themselves. This phenomenon is called annihilation radiation, which is the working foundation and principle of PET, as shown in Fig.2. The two opposite optical signals from annihilation radiation are examined by the detector. The detector converts the optical signal into an electrical signal. The computer calculates, processes the collected signals, and performs image reconstruction. Eventually, metabolic imaging of tissue and organ, as well as the distribution of tomography tracer images, is found^[18-19].

  Figure 2

  

  Figure 2.  Process of producing the phenomenon of annihilation radiation

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  1.3   Common radionuclide of PET

  The ¹⁸F chemistry is rapidly expanding due to the use of the radionuclide as a tracer for PET. ¹¹C, ¹³N, ¹⁵O, and ¹⁸F are common positrons of PET^[20-26]. Some of the positron emitters are listed in Table 1. Carbon, nitrogen, and oxygen are the most important elements in organisms and the main elements in the metabolism of life. However, its short half-life limits its application. Although the half-life of ¹³N is only 9.97 min, our group reported the application of three-dimensional PET/CT for the analysis of ¹³NO₃^- uptake and ¹³N distribution in growing kohlrabi, as shown in Fig.3.

  Table 1

  

  Table 1.  Common positron radionuclide

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  Radionuclide	11C	13N	15O	18F	22Na	38K	30P	194Au	52Mn	52Fe	56Co	64Cu	68Ga
  Half life	20.4 min	9.97 min	122 s	109.8 min	2.60 a	7.60 min	2.5 min	38.02 h	5.59 d	8.28 h	77.3 d	9.74 min	67.7 min
  Emax/MeV	0.96	1.2	1.73	0.63	0.55	2.7		1.47	0.58	0.8	1.46	2.93	1.92

  Figure 3

  

  Figure 3.  PET/CT images of kohlrabi ¹³NO₃^- uptake and distribution^[22]: (A) PET imaging for the time elapsed since the root supply of ¹³NO₃^-; (B) PET/CT imaging for the plant from the coronal direction; (C) PET imaging of another kohlrabi for ¹³NO₃^- uptake and ¹³N distribution; (D) Photograph of a test plant fixed on the scanner bed for PET/CT imaging

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  Introducing ¹⁸F to functionally complex molecules has been an outstanding achievement in nuclear chemistry. ¹⁸F is the most common radionuclide employed to fabricate various PET probes. ¹⁸F is produced through bombardment with ¹⁸O and [H₂O] in cyclotron^[27]. ¹⁸F has excellent physical and chemical properties. As a typical halogen element, fluorine has a strong oxidizing property. The positron energy is lower when the ¹⁸F decays, and the radioactive damage to the patient is smaller than other radionuclides. In addition, because of the low positron energy and short positron range, the spatial resolution of ¹⁸F is high. The most significant advantage of ¹⁸F is the ideal half-life (109.8 min). A long half-life in the body may cause great damage to the organism, and a short half-life hampers operation. ¹⁸F can be labelled with inorganic substances and organic compounds, and it can also be replaced by a hydrogen atom and hydroxyl group without destroying its biological activity. Finally, it is facile for the ease of production of ¹⁸F via cyclotron in large quantities at hospitals and laboratories. At present, ¹⁸F has been widely used in clinical medicine and the research field^[28-31].

  2.   PET probe

  2.1   PET probe of [¹⁸F]-2-deoxy-2-[¹⁸F]fluoro-D-glucose ([¹⁸F]-FDG)

  PET was first introduced in the 1970s. Since the perfect half-life, ¹⁸F has been widely used in PET in recent years^[32-35]. The ¹⁸F is a highly sensitive PET tracer for bone imaging. At present, ¹⁸F-labelled glucose as [¹⁸F]-FDG is the most advanced PET probe and is the most widely used in clinics for tumour detection, which is considered a century drug^[36-39]. Compared with normal cells, tumour has a higher glucose requirement due to the malignant proliferation. When [¹⁸F]-FDG is injected into the body of the patient, the intake of [¹⁸F]-FDG increases abnormally, and it actively accumulates in the region of the malignant tumour, which is quantitatively recorded by PET imaging with strong signals.

  The advantages of [¹⁸F]-FDG are obvious, including increasing water solubility, reducing the physiological intake of the digestive system, reducing of endothelium network removal, and extending retention time for target tissue. However, it also has certain disadvantages. Due to the strong polarity of glucose, it may change the polarity distribution of the labelled molecule and affect its ability. The spatial steric hindrance of glucose may affect the affinity. In essence, it is glucose metabolism imaging rather than specific tumour imaging. In some cases, it may show false-positive and false-negative results. In addition, although the [¹⁸F]-FDG probe has been widely used in clinics, one glucose molecule can only carry one ¹⁸F atom. The imaging contrast needs to be improved to obtain signal amplification. Furthermore, because of the naked ¹⁸F with leakage, it may cause a certain degree of radioactive hazard to the body. So far, the leakage of radionuclides is an important issue to be solved worldwide. Recently, the biggest challenge for [¹⁸F]-FDG in the clinic is the improvement of sensitivity and targeting because one glucose (FDG) molecule can carry only one F atom without active targeting. Maybe the glucose is labelled on the ferric oxide nanoparticles (NPs), and then ¹⁸F is labelled on glucose.

  Nowadays, it is witnessing the applications of the versatility of [¹⁸F]-FDG probe in various cancers. Furthermore, ¹⁸F-labelled glucose derivative and glucose analogue as probes have been experiencing an unprecedented expansion^[40-43]. It is reported that [¹⁸F]-FDG-based prosthetic group was synthesized for the chemoselectivity of ¹⁸F-labelling of peptides and proteins. [¹⁸F]-FDG was used as a building block for the synthesis of [¹⁸F]-FDG-maleimidehexyloxime, termed [¹⁸F]-FDG-MHO. The role of the [¹⁸F]-FDG-MHO probe is to extend the metabolic imaging function of [¹⁸F]-FDG to targeted PET imaging of peptides and proteins through chemoselective labeling strategies. The conversion of [¹⁸F]-FDG to [¹⁸F]-FDG-MHO was performed in organic solvent. The strong chemoselective conjugation between [¹⁸F]-FDG-MHO and the thiol group was investigated by the reaction with the tripeptide glutathione and cysteine. In addition, [¹⁸F]-FDG was used as a precursor to synthesize [¹⁸F]-FDG-RGD(Arg-Gly-Asp).

  2.2   PET probe of amino acid

  As components of proteins, amino acids are essential nutrients for the human body. Compared to normal cells, the metabolism of amino acids is strongly enhanced in tumours. ¹⁸F-labelled amino acid as PET probes can identify tumour tissue with inflammation or other lesion sites, and can remedy the deficiencies of [¹⁸F]-FDG to some degree^[44]. O-(2-¹⁸F-fluoroethyl)-l-tyrosine ([¹⁸F]-FET) is one of the most promising probes and is widely used in brain tumour imaging. [¹⁸F]-FET is useful for the delineation of gliomas^[45-47]. It plays a significant role in the diagnosis of intracranial tumours, determining the location and scope of the tumour, and the detection of tumour recurrence. Compared to [¹⁸F]-FDG, [¹⁸F]-FET has unique complementarity of tumour uptake. [¹⁸F]-FET can′t be ingested by inflammatory tissues, which avoids false-positive results. The metabolism of [¹⁸F]-FET is stable in vivo and has favourable pharmacokinetic properties. Beside [¹⁸F]-FET, 4-[¹⁸F]fluoro-l-m-tyrosine ([¹⁸F]-FMT)^[48-51], 6-[¹⁸F]fluoro-l-dopa ([¹⁸F]-FDOPA), and anti1-amino-3-[¹⁸F]-fluorocyclobutane-1-carboxylic acid ([¹⁸F]-FACBC)^[52-54], are common PET probes for amino acid. [¹⁸F]-FDOPA, [¹⁸F]-FMT, and [¹⁸F]-FACBC are dopamine metabolites and transporters, amino acid metabolites, and amino acid transporters, respectively. [¹⁸F]-FDOPA, [¹⁸F]-FMT, and [¹⁸F]-FACBC are used to detect brain glioma and neuroendocrine tumours, brain tumours and lung cancer, prostate cancer and brain glioma, respectively.

  2.3   PET probe of nucleic acid

  Nucleic acid is one of the most basic substances in life and is the raw material for the synthesis of DNA. According to labelling radionuclide on nucleosides, it can determine the proliferation, early diagnosis, and staging assessment of the tumour. Recently, 3′-deoxy-3′-[¹⁸F]fluorothymidin ([¹⁸F]-FLT), 2′-[¹⁸F]fluoro-5-methyldeoxyuracil-β-D-arabinof-uranosyl ([¹⁸F]-FMAU), and (2′-[¹⁸F]fluorodeoxyuracil-β-D-arabinof-uranosyl ([¹⁸F]-FAU)^[55-59] are employed as PET probes for nucleic acid metabolism. The probe has been exploited to assess the turnover of the DNA nucleoside thymidine and image tumour proliferation. The most advantage of [¹⁸F]-FLT is the proliferation-specific marker based on the measurement of cellular proliferation accurately with lower false positives. Furthermore, [¹⁸F]-FLT is more sensitive, and it can distinguish the differentiation between tumour and inflammation. [¹⁸F]-FMAU and [¹⁸F]-FAU have unique value in the assessment of tumour proliferation, viral infection imaging, and monitoring gene therapy by the synthesis pathways of targeting DNA. They are complementary to [¹⁸F]-FDG probes and can promote the development of precision medicine.

  2.4   PET probe of receptor

  Based on the peptide receptor, targeted PET imaging and therapy of cancer are at the forefront in nuclear medicine^[60-65]. The radiolabelled peptide for targeted PET imaging and therapy based on overexpression of receptors in tumour cells is at the forefront of PET. The current task is to develop a high-affinity peptide ligand with ¹⁸F for targeting overexpressed receptors in different types of cancer. Since most tumour cells can over-express certain specific receptors, radionuclide-labelled ligands are introduced to visualize the tumour. Vascular endothelial growth factor (VEGF)^[66-67], epidermal growth factor receptors (EGFR)^[68-71], RGD, and somatostatin (SST) receptors are common tumour receptors^[72-74].

  In recent years, a large number of articles have reported ¹⁸F-labelled tumour receptors as PET probes for imaging. EGFR is a transmembrane glycoprotein with tyrosine kinase activity. Studies have shown that there is abnormal expression of EGFR or enhancement in many tumours, such as lung cancer, stomach cancer, breast cancer, cervical cancer, and pancreatic cancer. EGFR is closely related to proliferation, angiogenesis, tumour invasion, metastasis, and prognosis of tumours. As an over-expressed receptor of VEGF, it is a synthetic peptide that is studied relatively in-depth. They mainly regulate the angiogenesis process by interacting with their receptors, VEGFR-1 and VEGFR-2. The combination of [¹⁸F]-FDG with the VEGF expression is superior in diagnosis. RGD is a short peptide and it is composed of arginine-glycine-aspartic acid^[75-79]. RGD is a site identified by the interaction of integrin and its ligand. In some tumours, certain integrin receptors are often specifically expressed. In addition, (3R, 5R)-5-(3-[¹⁸F]fluorophenyl)-3-{[(R)-1-phenylethyl]amino}-1-[4-(trifluoromethyl)phenyl]pyrrolidin-2-one) ([¹⁸F]-FPATPP) and [¹⁸F]-fluoronicotinic acid-labelled folate are employed to visualize tumour^[80-81]. [¹⁸F]-FPATPP specifically binds to the cannabinoid receptor (CB1R) in the central nervous system to image the distribution of CB1R, which provides a basis for neuroscience research.

  2.5   PET probe of gene expression

  As one of the oncological therapies, gene therapy is a promising approach. The challenge for gene therapy is to develop an online, non-invasive detection technique to monitor the size, location, and carrier-mediated gene expression in the human body. PET mainly focuses on reporting gene expression and in vivo tissue hybridization. Reporting genes can visualize the expression of specific endogenous or exogenous genes, as well as many intracellular biological phenomena, including special signaling pathways, nuclear receptor activities, and protein-protein interactions^[82-84]. At present, ([¹⁸F]-N-(4-fluorophenyl)-2-(1-phenyl-1H-benzimidazol-5-yl)acetamide) ([¹⁸F]pFBC) and [¹⁸F] fluoroetoxybenzo-vesamicol ([¹⁸F]-FEOBV) as PET probes are employed to image the reporting genes^[85-86]. [¹⁸F]-FEOBV is mainly used to evaluate the distribution and function of cholinergic nerve endings in the brain, especially in the study of neurodegenerative diseases, such as Alzheimer′s disease. The reported gene for PET probe generally refers to the substrate or ligand of a specific product, such as an enzyme, transporter protein. Currently, the gene expression can be combined with [¹⁸F]-FDG probe for tumour detection.

  2.6   PET probe of hypoxia

  Hypoxia represents the oxygen levels of the tumour-specific microenvironment in tissues. Because malignant tumour proliferation is faster than normal tumour, it leads to a significant requirement for oxygen and other materials. Due to the rapid tumour proliferation and rapid expansion in volume of the tumour, it leads a lack of blood supply. As a result, the tumour hypoxia occurs. Most malignant tumour tissues are low in oxygen, such as breast cancer, cervical cancer, pancreatic cancer, prostate cancer, and colon cancer.

  There has been increasing interest and efforts to detect the hypoxic region in the tumour. Polarography has been applied to monitor oxygenation by insertion of a needle electrode, with the invasive method, especially disrupting tissues. The non-invasive PET/CT imaging of hypoxia with nitroimidazole derivatives has been intensively investigated. The designed PET probe can selectively stay in the hypoxic tissue and diagnose, evaluate the tumour cells by analyzing the degree of hypoxia^[87-91]. As a PET probe of hypoxia, ¹⁸F-fluoroazomycinarabinoside ([¹⁸F]-FMISO) and ¹⁸F-fluoro-hydroxyl-xanthine ([¹⁸F]-FHX4) are popular with researchers, with the advantage of visualizing hypoxia. [¹⁸F]-FMISO is a nitroimidazole compound, and it can reflect the intracellular oxygen pressure. The uptake of [¹⁸F]-FMISO is negatively correlated with oxygen pressure in the tumour, which can accurately identify hypoxic areas and assist in the delineation of radiotherapy targets and dose optimization. [¹⁸F]-FHX4 is a novel anoxic imaging probe with optimized molecular design and pharmacokinetic properties, aiming to overcome the shortcomings of traditional nitroimidazole probes. Compared to [¹⁸F]-FMISO, [¹⁸F]-FHX4 clears normal tissue faster and can be finished within one hour after injection, significantly reducing examination time and improving the ratio of target/background. The main challenge in this field is to design and develop a smart probe with improved signal-to-noise and high sensitivity.

  3.   NPs for ¹⁸F PET probe

  3.1   Property of NPs for imaging probe

  Incorporation of common nuclides into NPs will pave the way for PET imaging, an evolutionary approach that leads to controlled in vivo circulation and tissue-selective targeting. Recently, various types of NPs for PET probes have provided a platform in biology, clinical medicine, and other fields, especially ¹⁸F-labelled NPs PET probes. The small spherical NPs as probes can easily pass through the cell barrier, which enables them to smoothly penetrate blood vessels and tissues. The uptake of nanoprobe via renal clearance and reticuloendothelial system (RES) by the kidney and liver is less than other molecules. Thus, the nanoprobe can prolong circulation time, and it is beneficial to reach the target. Due to the enhanced permeability and retention effect (EPR), the nanoprobe can selectively accumulate at the site of the tumour. These features enable the nanoprobe to be more preferable for imaging probes and for targeting the delivery of drugs. In addition, it is facile to synthesize NPs with a larger specific surface area and with ease of modification. Furthermore, nanoprobe can transport and deliver a large number of target reagents and therapeutic drugs as a vessel. NPs can be labelled with isotopes, receptors, and biological ligands, with image signals, targeting, and multiple pharmacokinetic properties. NPs possess internal packaging capacity and sufficient surface area for loading^[92-100]. Compared to a single molecule of the PET probe, a nanoprobe can significantly improve the detection signal and achieve high sensitivity.

  3.2   ¹⁸F-labelled NPs for PET probes

  In light of the short half-life of ¹⁸F, the quick labelling of ¹⁸F on NPs as PET probes with high reaction yields is necessary to improve the efficiency of the nuclide and reduce cost. Unfortunately, most of the methods are based on organic reactions, which suffer from harsh conditions, such as high temperature, long reaction times, large amounts of organic solvent, complicated separation and purification process, or even poor yields. Recently, NPs containing rare earth elements were the optimal candidate for labelling ¹⁸F, such as NaYF_4, NaGdF₄, NdF₃, YF₃, LaF₃, based on the strong interaction between F and rare earth ion^[101-102]. Hydroxyapatite (HAP) NP is also an excellent carrier for labelling ¹⁸F as a PET probe, which can be finished in a short time due to the unique structure of HAP. Our group has designed an ¹⁸F-HAP probe for PET imaging^[103]. Because the radius of the fluoride ion is similar to hydroxyl, the fluoride ion can replace the hydroxyl group. In previous reports, the immobilization of ¹⁸F was achieved by weak physical adsorption. In our group, ¹⁸F is directly doped in the process of synthesis of HAP with the advantage of signal amplification.

  4.   Supplementary PET probe

  Although the ¹⁸F-labelled probe has bloomed in the molecular imaging field, with the vision of creating more efficient probes, a large number of metals with chelation have been used to fabricate PET probes, such as ⁶⁴Cu, ⁶⁸Ga, ⁴⁴Sc, ⁸⁹Zr, ¹⁷⁷Lu, ⁹⁹Tc, ¹⁸⁸Re^[104-109]. Compared with ¹⁸F, the radioactive metal with a longer half-life enables it to be transported to slower biological processes. To successfully apply the metal to the image of biological processes, they must chelate an organic framework or bind to a targeting molecule. Some elements in the periodic table can be used for a PET probe, as shown in Fig.4^[110].

  Figure 4

  

  Figure 4.  Radionuclide imaging of trace metal^[110]

  Colour-coded to highlight elements in the periodic table can be used to image trace metals.

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  Due to the advantage of ⁶⁸Ga with a half-life of 67.7 min and dominantly decays of 1.92 MeV positron emission, it is frequently used as a PET probe^[111-117]. The production of ⁶⁸Ga comes from a ⁶⁸Ge-⁶⁸Ga generator, instead of cyclotrons, with the ease of availability, low costs, and magnetism. The coordination and biological properties of Ga are similar to Fe and V elements. Thus, the Fe with high biomolecule affinity can be easily attached to the Ga ligand exchange. ⁶⁸Ga is widely employed in the management of neuroendocrine, prostate, and lung cancer via favorable chemistry with tri- and tetraaza-ring molecules. Furthermore, ⁶⁸Ga is widely employed for RGD peptide imaging. The ⁶⁸Ga-labelled RGD derivatives can be applied to evaluate the effects of antiangiogenic treatment. Various ⁶⁸Ga-labelled RGD derivatives have been developed and applied in clinical and research settings.

  With a half-life of 12.7 h, significantly longer than ¹⁸F, ⁶⁴Cu has been applied for targeting motifs as antibodies with longer blood lifetime^[118-123]. ⁶⁴Cu is obtained in a cyclotron by bombarding an enriched nickel target (⁶⁴Ni). Due to the coordination numbers from 4 to 6, Cu(Ⅱ) can form stable complexes with biomolecules based on the Irving-Williams series, which can be explained with crystal field stabilization energy (CFSE) and Jahn-Teller effect. The biomolecular, especially macrocycle, such as 1, 4, 7, 10 tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid (DOTA), 1, 4, 7-triazacyclononane-1, 4, 7-triacetic acid (NOTA), 1, 4, 8, 11-tetraazacyclotetradecane-1, 4, 8, 11-tetraacetic acid (TETA), and folic acid show more stable than other chelating agent with copper, especially DOTA. DOTA, NOTA, and TETA often act as ligands and are used for metal chelation. Compared with ⁶⁸Ga, ⁶⁴Cu is suitable for tracking the temporal dynamics of biological processes due to its long half-life. ⁴⁴Sc is another radioactive metal with a half-life of 3.9 h, which can be employed for a PET probe^[124-126]. Both the generator and cyclotron can produce ⁴⁴Sc. The coordination number of ⁴⁴Sc ranges from 3 to 9, and 6 is the most common. DOTA and its derivatives are the common chelating agents for scandium. However, labelling occurs at high temperatures and long time. Researchers are looking forward to the fabrication of stable complexes under mild conditions. In addition, ⁴⁴Sc can emit both positron (diagnostic) and β-particle (therapeutic) properties, which are suitable for integrated diagnosis and treatment.

  5.   Multi-modality molecular imaging probe with ¹⁸F

  Although great achievements are achieved in PET probes^[127-128], ¹⁸F radiotracer and related applications are summarized and shown in Fig.5. A single imaging probe is not perfect and can′t be sufficient to obtain all the information with the limited sensitivity and resolution. PET has high sensitivity, unlimited penetration depth, and accurate quantitative analysis, but it is harmful to patients with nuclear radiation and high cost. MRI has higher resolution, unlimited tissue depth, but lower sensitivity. Ultrasound imaging has high tissue permeability and real-time monitoring, but it has low resolution. CT imaging has unlimited tissue depth, but it has lower sensitivity, high radiation damage, and it can′t be used for quantitative analysis. Optical imaging has high sensitivity, but it has low tissue penetration and spatial resolution. Multi-visualization techniques are a powerful tool in micro-quantitative molecular events, and it is critical to biomedical research and clinical diagnostics. The multi-imaging modalities provide a wealth of information that is highly complementary and rarely redundant.

  Figure 5

  

  Figure 5.  ¹⁸F-labelled radiotracers and the related applications^[127]

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  PET is superior to other imaging techniques. PET is the most sensitive and accurate molecular imaging technique with a versatile three-dimensional model. However, the PET lacks anatomical information. CT provides exceptional anatomical information, but suffers from limited sensitivity. Hence, the combination of PET-CT provides excellent spatial resolution and high sensitivity. The most important achievement is the complementary information of functional and anatomical images. The marriage of PET and CT has yielded an offspring to bring momentous advances in the fight against cancer^[129].

  Recently, rare-earth (RE) doped upconversion nanoparticles (UCNPs) have moved into the spotlight as an efficient platform for constructing multi-modal nanoprobes. Lanthanide elements such as Yb³⁺, Tb³⁺, and Er³⁺ are ideal candidates for multimodal bioimaging probes with unique luminescent properties due to the 5f electrons^[130-132]. Meanwhile, Gd³⁺, Yb³⁺, and Lu³⁺ doped in UCNPs with higher atomic number and stronger X-ray attenuation act as excellent CT and PET probes, fluorescent probes, and near-infrared (NIR) probes^[133-134]. Some RE ions, like Gd³⁺ ions with unpaired f electrons, show high paramagnetic relaxivity, have been used as contrast agents for MRI. ¹⁸F-labelled RE ions (Gd³⁺, Yb³⁺, Er³⁺), co-doped NaYF₄ NPs simultaneously possess radioactivity, magnetism, and upconversion luminescent properties for PET, MRI, and upconversion luminescence (UCL) imaging^[135]. The ¹⁸F is labelled UCNPs through a facile inorganic reaction based on the strong interaction between Y³⁺ and F^-, with high yield. In addition, Fe₃O₄ NPs can also be introduced into the UCNPs for imaging with ease of separation^[136]. As a result, multi-modal imaging techniques including MRI, CT, PET, and UCL imaging have been rapidly developed via integration of doped ions^[137]. The images of the UCNPs for NMR, PET, and UCL imaging in mice are shown in Fig.6^[138].

  Figure 6

  

  Figure 6.  Schematic illustration of the UCNPs for multimodal imaging, detection of ROS, and therapy^[138]

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  6.   Approach for ¹⁸F-labelled PET probe

  The past decade has witnessed the emergence of a new strategy based on the formation of ¹⁸F-labelled material as a PET probe. Specific and affinity tumour markers and some living substances such as oligonucleotides, purines, active oxygen species (ROS), carbohydrate derivatives, and hydrazone are employed to construct a PET probe for tumour detection. Recently, the development in approach and strategies of ¹⁸F-labelled molecules as PET imaging agents has been reported^[139-140]. The conjugation of ¹⁸F to the target molecule generally requires multiple steps, under harsh conditions, and tedious purification processes. The introduction of ¹⁸F involves nucleophilic/electrophilic fluorination, isotope exchange fluorination, halogen exchange methodology, aluminum-fluoride (Al¹⁸F) complex labeling, transition metal-mediated cross-coupling of ¹⁸F, click chemistry/bioorthogonal reactions^[141-142]. Among these methods, electrophilic and nucleophilic fluorination are the main and relatively widely-used approaches. The nucleophilic/electrophilic fluorination includes aliphatic nucleophilic fluorination, aromatic ring/ heteroaromatic ring fluorination, diaryliodonium salt fluorination, iodonium ylide-mediated fluorination, and transesterification labelling. The precursor (¹⁸F-KF), together with the phase transfer catalyst amino crown ether polyether, can directly introduce an ¹⁸F atom into the target molecule for aliphatic nucleophilic fluorination^[143]. Balz-Schiemann reaction and Wallach reaction are used to label electron-rich arene^[139]. Due to the low risk of defluorination, the ¹⁸F-labelled aromatic ring/heteroaromatic ring PET imaging agent is available. Because the heteroarenes are more electron-deficient than the corresponding aromatic hydrocarbons due to the incorporation of nitrogen. Thus, heteroarenes are amenable to direct substitution for ¹⁸F-fluoride^[144]. Due to the special and unbalanced electronic configuration of diaryliodonium salt, ¹⁸F tends to be labelled on it. However, compared to diaryliodonium salts fluorination, iodonium ylide-mediated fluorination is facile for labelling ¹⁸F on aromatic ring compounds because of its high selectivity^[140]. For halogen exchange fluorination, bromine, chlorine, and iodine can be replaced by fluorine atoms due to their similar physicochemical properties. Some special molecule containing an activated carboxyl can be used to label ¹⁸F through a transesterification reaction based on the similar radius of fluorine and hydroxyl^[103]. In addition, some elements such as Al, Si, and B are introduced for binding ¹⁸F based on the strong complex reaction with F. The fluoride ion chelates with Al, Si, B, and the resulting [Al-¹⁸F], [B-¹⁸F], [Si-¹⁸F] complexes with different macrocyclic chelators^[145]. Click chemistry is a powerful approach and strategy in the synthesis of PET imaging probes, and it occurs in cycloaddition and nucleophilic ring-opening reactions under relatively mild conditions^[146-147]. Thus, it is suitable for ¹⁸F to label pharmaceuticals. Furthermore, difluorocarbene-enabled synthesis has been developed as a new approach for making ¹⁸F-radiotracers^[148]. Transition metal-mediated cross-coupling reactions that result in the coupling of aromatic rings or the addition of nucleophiles to aromatic rings have been a significant application in fluorination. Apart from this, chemical, enzymatic method, oxime method, and sulfhydryl compound linking method are employed to design the PET probe^[149]. It is believed that with the improvement of novel approaches, more ¹⁸F-labelled materials as PET probes will be applied in the diagnosis and treatment of tumours.

  7.   Discussion and future perspectives

  Great progress has occurred in PET imaging, not only in the advanced equipment, but also in the ¹⁸F PET probe. In the paper, ¹⁸F-labelled chemical agents as PET imaging probes are summarized in detail, which puts forward a prospective strategy to fabricate a PET probe and apply it in clinical settings. The past decade has witnessed the rapid development of the ¹⁸F PET probe. However, the advances have not translated into greatly improved preclinical outcomes. It is necessary to fabricate a smart PET probe and apply it in clinical medicine. In the future, the PET probe tends to more sensitively monitor interactions at a molecular level, with sufficiently high sensitivity and spatial resolution, and detection of tumours as early as possible. In addition, it is necessary to design a multifunctional imaging probe with noninvasive therapy. Many factors, such as biocompatibility, radionuclide leakage, pharmacokinetics, long labelling time, and targeting efficacy, should be taken into consideration before clinical use. To improve biocompatibility and avoid leaks, the encapsulation technique is the optimal candidate. The development of novel ¹⁸F-labelled approaches, strategies, and synthetic routes to achieve shorter operating times and improve targeting efficacy is very important. The probe of synthesis influences the formation of structure, the structure of the probe determines properties, and the applications of the probe depend on properties. Therefore, the synthesis of the probe is of utmost significance. In order to apply in clinical settings, we must make great efforts in synthesis. Novel approaches should be developed, and modifications of functional groups should be carried out, which endow the probe with more functions and unique properties. Ultimately, clinical application will be achieved, and the quality of life for humans will be improved.

  
  Acknowledgements: This work was financially supported by the Key Research and Development Plan of Shaanxi Province (Grant No.2024GX-YBXM-318), the "Four Chains" Integration of the Total Window of Shaanxi Innovation and Creation Platform (Grant No.2024PT-ZCK-38), Department of Science and Technology Project of Shaanxi Province (Grants No.2025JC-YBMS-146, 2025SF-YBXM-475), National Natural Science Foundation of China (Grant No.22177066). Author contribution: WU Rui: Conceptualization, methodology, writing-main review, investigation, validation, & editing, proof, project administration. ZHANG Yankun: Resources, supervision. LU Jiufu, ZHANG Pengfei: Literature search. WANG Yang: Formal analysis. All the authors reviewed the manuscript.
  Consent to participate: All the authors consent to participate in this article.
  Declarations
  Consent to publication: All the authors consent to publish this article.
  Competing interests: The authors declare no competing interests.
  Data availability statement: All data generated or analyzed during this study are included in this article.
  
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• 

  Figure 1  Close relationship between health and disease, lifestyle, and disease management^[1]

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  Figure 2  Process of producing the phenomenon of annihilation radiation

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  Figure 3  PET/CT images of kohlrabi ¹³NO₃^- uptake and distribution^[22]: (A) PET imaging for the time elapsed since the root supply of ¹³NO₃^-; (B) PET/CT imaging for the plant from the coronal direction; (C) PET imaging of another kohlrabi for ¹³NO₃^- uptake and ¹³N distribution; (D) Photograph of a test plant fixed on the scanner bed for PET/CT imaging

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  Figure 4  Radionuclide imaging of trace metal^[110]

  Colour-coded to highlight elements in the periodic table can be used to image trace metals.

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  Figure 5  ¹⁸F-labelled radiotracers and the related applications^[127]

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  Figure 6  Schematic illustration of the UCNPs for multimodal imaging, detection of ROS, and therapy^[138]

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  Table 1.  Common positron radionuclide

  Radionuclide	11C	13N	15O	18F	22Na	38K	30P	194Au	52Mn	52Fe	56Co	64Cu	68Ga
  Half life	20.4 min	9.97 min	122 s	109.8 min	2.60 a	7.60 min	2.5 min	38.02 h	5.59 d	8.28 h	77.3 d	9.74 min	67.7 min
  Emax/MeV	0.96	1.2	1.73	0.63	0.55	2.7		1.47	0.58	0.8	1.46	2.93	1.92

  下载: 导出CSV
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