key: cord-0902025-kclb33nd authors: Hu, Ji; Li, Hongyu; Sui, Yanying; Du, Jin title: Current status and future perspective of radiopharmaceuticals in China date: 2021-11-12 journal: Eur J Nucl Med Mol Imaging DOI: 10.1007/s00259-021-05615-6 sha: d4faa2477b422b8f4aae5e19d8fae0b0897cd8f0 doc_id: 902025 cord_uid: kclb33nd Radiopharmaceuticals are essential components of nuclear medicine and serve as one of the cornerstones of molecular imaging and precision medicine. They provide new means and approaches for early diagnosis and treatment of diseases. After decades of development and hard efforts, a relatively matured radiopharmaceutical production and management system has been established in China with high-quality facilities. This review provides an overview of the current status of radiopharmaceuticals on production and distribution, clinical application, and regulatory supervision and also describes some important advances in research and development and clinical translation of radiopharmaceuticals in the past 10 years. Moreover, some prospects of research and development of radiopharmaceuticals in the near future are discussed. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00259-021-05615-6. The research and production of medical radioisotopes and radiopharmaceuticals in China began in the 1950s [1] . In 1958, the first heavy water reactor and the first accelerator were built and put into use in China at the China Institute of Atomic Energy (CIAE). The first batch of 33 radioisotopes including 24 Na, 32 P, 60 Co, and 131 I were successfully developed, thus initiating the undertakings of the production and application of radioisotopes and radiopharmaceuticals in China. Since the late 1950s, 131 I has been widely used in the diagnosis of thyroid function and radionuclide therapy for hyperthyroidism and thyroid cancer, and 32 P has been applied for the treatment of polycythemia vera and the control of cancerous pleural effusion and ascites, which pioneered the application of radioisotopes in clinical diagnosis and treatment in China. Since the 1970s, China has committed to the development of the technologies on production of key medical radioisotopes such as 131 I, 125 I, 32 P, 99 Mo, and 99m Tc. For example, two types of 99 Mo/ 99m Tc generators (fission and gel) were successively developed with stable manufacturing technique and established good manufacturing practice (GMP) facilities to meet the domestic market demand to a certain extent [2, 3] . Currently, there are five nuclear reactors in service in China for research purposes, and their associated facilities have been used for the production of medical radioisotopes such as 99 Mo, 125 I, 131 I, 32 P, 177 Lu, 89 Sr, and 153 Sm. Among above five reactors, two of them are located in Beijing, and the other three are located in the Southwest China. However, because of various factors, only a small amount of 131 I has been produced since 2008, and the supply of other reactor-produced medical radioisotopes has heavily relied on importing abroad. As a comparison, accelerator-produced radioisotopes have been largely developed in China. As of 2020, three 30 MeV cyclotrons and more than 120 small medical cyclotrons have been installed for the production of radionuclides such as 18 F, 123 I, and 64 Cu. The great progress on research and development of radiopharmaceuticals in China has been made during the course of more than half a century of growth [4] . Until now, over 40 radiopharmaceuticals involving 12 types of radionuclides After decades of development, radiopharmaceutical industry in China has made great progress; the whole industry chain integrating research, production, sales, and application has been established; and the market scale has continued to grow [5] . At present, the companies engaged in production and sales of radiopharmaceuticals in China mainly include China Isotope & Radiation Corporation and its subsidiaries HighTech Atom Co., Ltd. (HTA) and Chengdu Gaotong Isotope Co., Ltd. (Chengdu Gaotong), Dongcheng Pharmaceutical Group Co., Ltd. and its subsidiary Dongcheng AMS Pharmaceutical, Jiangyuan Pharmaceutical Factory of Jiangsu Institute of Nuclear Medicine, and Beijing Shihong Pharmaceutical Co., Ltd. of Beijing Normal University. The radiopharmaceuticals commercially available in China are summarized in the Table 1 . It indicates that only a limited number of radionuclides and radiopharmaceuticals are currently produced and supplied in China, and the demand of clinical nuclear medicine is not fully met yet. Because of the short half-life of 99m Tc (6.0 h) and 18 F (109.7 min), medical institutions can prepare such radiopharmaceuticals on their own for nuclear medicine clinical application. A more common option is to rely on commercial radiopharmaceutical production centers (also known as centralized radiopharmacy) that meet GMP standards for instant radiolabeling, production and distribution. To date, there are around 50 centralized radiopharmacies built by large radiopharmaceutical companies such as HTA and Dongcheng AMS Pharmaceutical that are running in the large-and medium-sized cities in China for production and distribution of 99m Tc-labeled radiopharmaceuticals and positron radiopharmaceuticals including [ 18 F]FDG (refer to Fig. 1 ). In addition to these commercial centralized radiopharmacies, large medical institutions equipped with cyclotrons independently produce [ 18 F]FDG and other 11 C-, 15 N-, and 18 F-labeled positron radiopharmaceuticals for clinical research in accordance with the requirements of Regulations on the Preparation of Positron Radiopharmaceuticals in Medical Institutions issued by the NMPA. As the nuclear medicine industry in China continues to grow, more centralized radiopharmacies need to be built to achieve extensive coverage and meet the pace of nuclear medicine development. It is estimated that by 2025, about 50 new centralized radiopharmacies will be built across the country, and the availability and accessibility of radiopharmaceuticals will be significantly improved by then. In recent years, because of the successful application of targeted radiopharmaceuticals in the clinical diagnosis and treatment, the radiopharmaceuticals industry has gradually become the focus of attention among financial capitals and innovative pharmaceutical companies. Some traditional pharmaceutical companies, such as Dongcheng Pharmaceutical Co. Ltd., Sinotau Pharmaceuticals, and Hengrui Pharma, have begun to set foot in the radiopharmaceutical industry and started research, development, and production of radiopharmaceutical. This will further boost the development of the radiopharmaceutical industry in China. In April 2020, the Chinese Society of Nuclear Medicine carried out a biennial national census on current status of nuclear medicine in China [6] . The number of nuclear imaging cameras and clinical nuclear medicine practices in China are illustrated in Fig. 2 . The result highlights that as of December 2019, there are 1148 departments (sections) engaged in nuclear medicine practices, 770 (67.1%) of Up to now, there are 2544 beds in total dedicated to radionuclide therapy in all the medical institutions that carry out radionuclide therapy across China. Nearly 530,000 treatments have been conducted annually, among which 131 I treatment of Graves' hyperthyroidism accounts for 27.6%, and 90 Sr/ 90 Y applicator treatment for skin and eye diseases 25.5%, 99 Tc-methylene bisphosphonate treatment for rheumatoid arthritis 18.6%, 131 I treatment of differentiated thyroid cancer 15.9%, 32 P application treatment 6.6%, radioactive seed interstitial implantation treatment 2.4%, and 89 Sr for bone metastasis 2.0%. In recent years, some medical institutions have begun to use [ 223 Ra]RaCl 2 for the treatment Fig. 1 The production and distribution network of radiopharmaceuticals in China. Centralized radiopharmacy refers to the production center for the diagnostic radiopharmaceuticals with radionuclides having shorter half-life, such as 99m Tc and 18 F. Radiopharmaceutical production base refers to the factory for the production of medical radioisotopes and the production of diagnostic and therapeutic radiopharmaceuticals labeled with radionuclides having longer half-life of castrated prostate cancer patients with bone metastases, and some therapeutic radiopharmaceuticals such as [ 177 Lu] Lu-DOTA-TATE, [ 177 Lu]Lu-DOTA-TOC, and [ 177 Lu]Lu-PSMA have also been prepared and investigated for the clinical research of neuroendocrine tumors and prostate cancer. Radiopharmaceutical administration in China has gone through a long process of continuous improvement. In the 1950s to 1960s [7] , radiopharmaceuticals were regulated as medical radioisotopes. It was not until 1974 that radiopharmaceuticals began to be regulated as pharmaceuticals. The 1977 edition of Chinese Pharmacopoeia included radiopharmaceuticals for the first time. In 1989, the State Council of China promulgated the Measures for the control of Radioactive Drugs, ushering in an era of lawbased administration of radiopharmaceuticals in China. In 2017, the Measures for the control of Radioactive Drugs was revised. The provisions on the development, clinical research and approval, production, operation, import and export, packaging and transportation, and use of radiopharmaceuticals were provided. A radiopharmaceutical production and handling enterprise must hold the "Radiopharmaceutical Production License" and/or the "Radiopharmaceutical Handling License". To be able to use radiopharmaceuticals, medical institutions must obtain a "Radiopharmaceutical Using License". Currently, the state authority responsible for the supervision and registration of radiopharmaceuticals is the NMPA and its directly affiliated units, comprising mainly of the Department of Drug Registration, the Center for Drug Evaluation (CDE), the National Institutes for Food and Drug Control, Center for Food and Drug Inspection (CFDI), and the Chinese Pharmacopoeia Commission (refer to Fig. 3 ). Radiopharmaceutical In 2006, the NMPA promulgated the Regulations on the Administration of the Preparation of Positron Radiopharmaceuticals by Medical Institutions, which regulates in explicit terms on the licensing conditions for the use and preparation of radiopharmaceuticals in medical institutions. The licenses are classified into four levels: a class I or a higher level license should be held for the use of radioimmunoassay kits for in vitro diagnosis; a class II or a higher level license should be held for the use of radiopharmaceuticals; a class III or a higher level license should be held for the preparation of radiopharmaceuticals; and a class IV license should be held for the development and related clinical research of new-type of radiopharmaceuticals, meanwhile a filing application should be submitted to the NMPA. The introduction and use of a new type of radiopharmaceuticals without marketing authorization in medical institutions are mainly through the pathway of investigator-initiated clinical studies. Investigators should submit the complete preclinical study data to the Clinical Research Management Committee and Ethics Committee for approval of a limited number of patient clinical studies which are not for the purpose of seeking marketing authorization. Furthermore, the preparation of relevant radiopharmaceuticals in medical institutions shall be carried out in accordance with good manufacturing practice for pharmaceutical products, and the radiopharmaceuticals prepared in medical institutions for clinical studies are for local in-house use only. In light of the fact that radiopharmaceuticals are usually with short physical half-life, the NMPA has successively issued the related documents such as Guidelines for Technetium [ 99m Tc] Radiopharmaceutical Quality Control and Guidelines for Positron Radiopharmaceutical Quality Control. In 2019, the newly revised Drug Administration Law of the People's Republic of China and Provisions of Drug Registration were issued, under which the marketing authorization holder (MAH) system was implemented. The regulation of clinical trials for new pharmaceuticals was reformed from the previous approval system into implied licensing. These revised regulations are also applicable to radiopharmaceuticals, presenting new opportunities to radiopharmaceutical innovation. Since 2020, the NMPA has successively issued the Technical Guidelines for Clinical Evaluation of Diagnostic In recent years, the preparation techniques of some major medical radioisotopes such as 99 Mo (LEU, low enriched uranium), 177 Lu, 64 Cu, 123 I, 89 Zr, and 211 At have been developed using reactors or cyclotrons, and some new progresses and breakthroughs have been achieved in China. CIAE developed the production procedure of fission 99 Mo with an emphasis on LEU target [8] [9] [10] . UO 2 layer was electroplated on inner wall of a hollow stainless cylinder. After dissolution, radiochemical extraction, and further purification processes, the final 99 Mo solution can meet the requirements for medical usage. CIAE also established the separation process of fission 99 Mo using Al 2 O 3 chromatography. The recovery yield of 99 Mo was more than 90%, and the decontamination effectiveness of the impurities such as Ru, Sr, Zr, Te, and Cs was more than 99.99%, and more than 92% of 131 I could be removed. 177 Lu-labeled radiopharmaceuticals can be used in the treatment of primary and metastatic tumor and palliation of bone pain caused by metastases. In recent years, the continued improvement of 177 Lu preparation technology has further promoted the development of 177 Lu radiopharmaceuticals. Relying on China Mianyang Research Reactor (CMRR), China Academy of Engineering Physics has developed technology and production facilities for 177 Lu, and it represents the first success in China to develop the production technology on no-carrier-added 177 Lu [11] . Small batch production (curie level) was achieved, and the product has been used in clinical trials at some hospitals. In the meantime, Chengdu Gaotong has signed a technology licensing agreement with Isotopen Technologien München Group in Germany, and it will implement the development and GMP-grade production of no-carrier-added 177 Lu of up to one hundred curies scale in China. 64 Cu could form a perfect theranostic nuclide pair with 67 Cu, and combining with its favorable properties makes 64 Cu a radioisotope of choice for clinical application of PET with unique advantages. Based on Cyclone-30 cyclotron and after a series of improvements on production process, HTA has established an automated process for 64 Cu production through 64 Ni(p,n) 64 Cu reaction with batch capacity greater than 74 GBq and the radionuclide purity of the product greater than 99.9% [12, 13] , and the product has been provided to a number of research institutions. Also based on Cyclone-30 cyclotron, using high abundance (> 99.8%) 124 Xe gas as target, HTA achieved the mass production of 123 I via 124 Xe(p,2n) 123 Cs(β + ) 123 Xe(EC, β + ) 123 I reaction, and the batch activity could reach 111 ~ 148 GBq, and the irradiation yield was greater than 296 MBq/(μA·h) [14] . 123 I has been routinely produced and supplied by HTA domestically since 2017. Based on CS-30 cyclotron, Sichuan University explored a simple and convenient method for radiochemical separation of 89 Zr with no harmful substance [15] . The radionuclidic purity of separated 89 Zr in the form of [ 89 Zr]Zr-chloride was 99.99%, and the recovery rate was 85% ± 3%. The yields of 89 Zr via the reaction of (p,n) or (d,2n) on Y target were also evaluated, and the latter one was proved to be more favorable for the production of 89 Zr with a yield of 58 ± 4 MBq/μA·h. Sichuan University also conducted research on the preparation of alpha particle emitting radioisotope 211 At using CS30 cyclotron via 209 Bi(α,2n) 211 At reaction [16] . Bismuth target was prepared by electroplating method. Using a homemade high-temperature dry distillation still, around 200 MBq of 211 At was isolated, with the ratio of 211 Po/ 211 At less than 10 −8 . Over the last decade, tremendous progress has been made in the development of novel radiopharmaceuticals by a large number of universities, hospitals, and research institutions in China. Numerous publications in this topic have become available in the literature, including a recent manuscript in Nature [17] and increasing number of publications in EJN-MMI [18] [19] [20] [21] [22] [23] [24] . The trajectory has displayed a major upward trend over the last decade, which clearly showed that this is a highly vibrant field. A comprehensive summary of the progress in the development of novel radiopharmaceuticals in China over the last decade is far beyond the scope of this review article, and interested authors are referred to these excellent review articles for more details [4, 25] . Below, we will only briefly mention a few representative tracers and therapeutic radiopharmaceuticals for various applications in cancer and other diseases. Patients with Alzheimer's disease (AD) present with both extracellular amyloid-β (Aβ) plaques and intracellular tau-containing neurofibrillary tangles in the brain [26] . Therefore, Aβ plaques and Tau protein are important pathological features of AD, which are considered to be the important targets for early diagnosis of AD. Cui et al. reported the design and synthesis of a series of PET probes for Aβ plaque imaging [27] [28] [29] [30] [31] [32] . Among them, [ 18 F]Florbetazine, which has a new molecular structure of dihydrazone, demonstrates suitable pharmacokinetic properties including high initial brain uptake and fast brain clearance in rodents and non-human primates, and it also shows comparative affinity compared to the Food and Drug Administration (FDA) approved [ 18 [20] . The AD patients have high retention in cortical regions, while healthy control subjects have uniformly low radioactivity uptake. A chiral 2-fluoromethyl-1,2-ethylenediol side chain was attached to the 2-phenylquinoxaline backbone to increase hydrophilicity of the compound, thereby improving the binding affinity and selectivity of the probe toward Tau tangles on β-amyloid plaques (Aβ). Quantitative binding assays with AD homogenates show that the probes (R)-1-fluoro-3-(4-(6-(methylamino)quinoxalin-2-yl)-phenoxy)propan-2-ol ((R)-5) and (S)-1-(4-(6-(dimethylamino)quinoxalin-2-yl) phenoxy)-3-fluoropropan-2-ol ((S)-16) have high affinity (K i = 4.1 and 10.3 nM, respectively) and high selectivity (30.5-fold and 34.6-fold, respectively) for Tau tangles [33] . In addition, they display sufficient blood-brain barrier penetration (7.06% and 10.95% ID/g, respectively) and suitable brain kinetics (brain 2 min /brain 60 min = 10.1, 6.5, respectively) in normal mice. These results demonstrate that (R)-[ 18 Sigma-1 (σ1) receptors are proved to be related to brain dysfunction and tumors as well as heart failure. Development of specific radiotracers for σ1 receptor imaging may provide useful diagnostic tools for investigation of their pathophysiology [34] . Jia's group designed and synthesized a range of new 18 F-labeled compounds that show potential for imaging σ1 receptor, including benzylpiperazine derivatives such as 1-(4-18 F-fluorobenzyl)-4-((tetrahydrofuran-2-yl)methyl) piperazine [35] , 4-phenylpiperidine-4-carbonitrile derivatives [36] , 1,4-dioxa-8-azaspiro [4, 5] decane derivatives [37] , and 1-oxa-8-azaspiro [4.5] decane derivatives [38] . [ 18 F] FBFP was synthesized in one step from an iodonium ylide precursor, and it possesses higher regional non-displaceable binding potential (BPND) values across the brain regions compared with (S)-[ 18 F]fluspidine [39] . [ 18 F]FBFP displays high brain uptake and suitable tissue kinetics for quantitative analysis in cynomolgus monkeys. Myocardial perfusion imaging is a well-established noninvasive method for diagnosing coronary artery disease. Recently, Zhao et al. reported the optimization of biodistribution properties of radiotracers [ 99m Tc]TcCl(CDO) (CDOH) 2 B-R] (CDOH 2 = cyclohexanedione dioxime) using different boronate caps [40] . Among these 11 new 99m Tclabeled radiotracers, [ 99m Tc]Tc-3SPboroxime [R = 3SP; 3-(methylsulfonyl)pyridine] shows the most promising characteristics as an optimal heart imaging agent. The SPECT image quality with [ 99m Tc]Tc-3SPboroxime in SD rats is better than that with [ 99m Tc]Tc-teboroxime. High heart uptake and long myocardial retention of 99m Tc-3SPboroxime have been confirmed in swine models [41] . Zhang et al. reported three novel 18 F-labeled pyridaben analogues (Fmpp1, Fmpp2, and Fmpp3) for potential myocardial perfusion imaging [42] . In the whole-body PET/ CT images of mini-swine, [ 18 F]Fmpp2 shows excellent initial heart standardized uptake value (SUV) (7.12 at 5 min p.i.) and good retention (5.75 at 120 min p.i.). The heart/ liver SUV ratios are 4.12, 5.42, and 5.99 at 30, 60, and 120 min after injection, respectively. The favorable biological properties of [ 18 F]Fmpp2 suggest that it is worth further investigation. Prostate-specific membrane antigen (PSMA) is overexpressed on the surface of the most of prostate cancer cells, and this expression of PSMA increases in low differentiated, metastatic, and androgen-independent prostate cancer cells. Therefore, PSMA is a promising target for diagnosis and therapy of prostate cancer [43] . In an effort to seek novel agents targeting PSMA, based on oxalyldiaminopropionic acid (ODAP), 16 ligands with structural modifications in PSMA S1′ binding pocket were synthesized and evaluated for PSMA inhibition by Duan et al. (S)-3-(carboxyformamido)-2-(3-(carboxymethyl)ureido) propanoic acids prove to be potent PSMA ligands with Ki values ranging from 0.08 to 8.98 nM [44] . Twelve ODAPurea-based ligands were synthesized and radiolabeled with 68 Ga [22] . Liu et al. reported a novel PSMA inhibitor, 6-hydrazinonicotinate-amino-caproic acid-lysine-urea-glutamate (HYNIC-ALUG), which was labeled with 99m Tc [45] . Preliminary clinical results show that this probe can be used to guide surgical procedures to remove more metastatic lymph nodes, and it can be of great value for response assessment and prediction of the effectiveness of treatment in metastatic castration resistance prostate cancer (mCRPC) patients after long-term abiraterone treatment. Based on the Glu-Ureido-Lys binding motif, three 18 F-labeled PSMA tracers with a more lipophilic quinoline functional spacer were designed, synthesized, evaluated, and compared with [ 18 F]DCFPyL by Zhang et al. [46] . There is no significant correlation between the renal elimination and the lipophilicity of the tracers in all species. However, the more lipophilic of the tracer was, the more radioactivity accumulated in the liver of primate and human, and the fewer radioactivity was to be excreted to the bladder with urine. The screened tracer [ 18 F]8c, with a K i value of 4.58 nM, displays notable low bladder retention and demonstrates good imaging properties in patients with prostate cancer. The integrin α v β 3 is highly expressed in neovascular epithelium of various tumors, which is a highly potential target for tumor diagnosis and therapy, and tripeptide sequence of arginine-glycine-aspartic acid (RGD) is the specific ligand which can be combined to integrin α v β 3 [47] . Researchers in China have made great effort on the exploration of RGD peptides labeled with [ 18 F]AlF, 68 Ga, and 99m Tc, such as [ 18 F]F-Alfatide injection [48] , [ 68 Ga] Ga-cycratide [49] , [ 68 Ga]Ga-NOTA-PEG3-β-Glu-RGD [50] , [ 99m Tc]Tc-3PRGD2 [51] , and [ 99m Tc]Tc-RWY [52] . Among them, [ 18 F]F-Alfatide injection used for the diagnosis of tumor lymph metastasis is carrying out phase II study, and [ 99m Tc]Tc-3PRGD2 injection used for benign and malignant diagnosis of lung tumors and diagnosis of lymph node metastasis is in the phase III study. In recent years, along with the clinical success of tumor immunotherapy, it is very important to screen the beneficiaries, predict the efficacy of drugs, and guide the clinical treatment during the immunotherapy. Accurate detection of PD-1/PD-L1 can be used to screen patients most likely to be responsive to PD-1/PD-L1 immunotherapy and to distinguish reactive tumors from refractory tumors at an early stage [53] . Using a single-domain antibody, NM-01, against PD-L1, radiolabeled site specifically with 99m Tc for SPECT, Xing et al. conducted early phase I study in non-small cell lung cancer, which demonstrates that 99m Tc-labeled anti-PD-L1-single-domain antibody SPECT/CT imaging is safe and associated with acceptable dosimetry [54] . Tumor uptake is readily visible against background tissues, particularly at 2 h when the primary tumor-to-blood-pool ratios (1.24 to 3.53 (mean, 2.22)) correlate with PD-L1 immunohistochemistry results (r = 0.68, P = 0.014). Miao Yang's group also conducted a first-in-human study of [ 68 Ga]Ga-NOTA-WL12 (a PD-L1-binding peptide radiotracer) demonstrating the safety and feasibility of the tracer for the detection of the tumor PD-L1 expression levels [59] . To seek novel 99m Tc-labeled glucose derivatives as tumor imaging agents, Zhang's group reported the synthesis and evaluation of a series of 99m Tc-labeled D-glucosamine derivatives with isonitrile as a coordinating group; among them, [ 99m Tc]Tc-CN7DG shows the highest tumor uptake and tumor-to-background ratios in the biodistribution and SPECT/CT studies in mice bearing A549 tumor xenografts [60] . [ 99m Tc]Tc-CN5DG could be readily prepared by using a CN5DG kit (Fig. 4) and was further studied in U87MG, HCT-116, PANC-1, and TE-1 tumor xenografts mice models to verify its potential application for imaging of different kinds of tumors (Fig. 5) [61, 62] . The biodistribution data shows that the tumor/muscle ratios (from 4.08 ± 0.42 to 9.63 ± 3.53) and tumor/blood ratios (from 17.18 ± 7.40 to 53.17 ± 16.16) of [ 99m Tc]Tc-CN5DG in four tumor models are high. These results demonstrate that [ 99m Tc]Tc-CN5DG may become a broad-spectrum SPECT probe for tumor imaging. Phase I clinical trial of this agent is in progress. Liu's group developed 18 [63, 64] . PET study demonstrates that these probes show remarkable and selective tumor uptake in BGC-823 and 4T1 xenografts, respectively. 18 F-trifluorobborate-derived tyrosine (denoted as [ 18 F]FBY), a PET tracer with favorable dosimetry profile and pharmacokinetics, was also developed, which shows potential to assay large neutral amino acid transporter type-1 (LAT-1) expression in glioma patients and may provide imaging guidance for further boron neutron capture therapy of gliomas [65] . [ 18 F]FBQ-C 2 was designed by adding two more methylene groups to the side chain of 18 [66] , which seems to be a better potential PET tracer than [ 18 F]FDG for brain glioma imaging with good visualization and ability to assess the tumor activity, and they also confirmed that excitatory amino acid carrier 1 is an important transporter of [ 18 F]FPGLU in oncologic PET. Besides the tumor imaging agents mentioned above, other tumor targeting radiotracers for imaging of hypoxia and a variety of tumor receptors have also been extensively explored which including: radiolabeled nitroimidazole derivatives for hypoxia imaging such as [ 64 [70, 71] ; 18 F-labeled ethisterone derivative [ 18 F]FPTT for imaging of progesterone receptor-positive breast cancer [72] ; 18 F-labeled isonicotinamide-based radioligands for investigating the glycogen synthase kinase-3β (GSK-3β) levels [73] ; [ 18 F]FP-Lys-GE11 for imaging of the epidermal growth factor receptor (EGFR) over expressed tumor [74] ; [ 18 F]-5-fluoro-N-(2-(Diethylamino)ethyl) picolinamide ([ 18 F]5-FPN) for the detection of metastatic lymph node and metastatic pulmonary lesions of melanoma [75] ; [ 99m Tc]Tc-HYNIC-Polypeptide-PEG 11 -Tz(1,2,4,5-tetrazine) and cetuximab-TCO for the pretargeted imaging of human colon cancer tumor [76] ; [ 68 Ga]Ga-NOTA-Nb1053 for visualizing multiple myeloma niduses [19] ; and [ 99m Tc]Tc-HYNIC-H10F for imaging of HER2-positive tumors [77] . Some radiotracers targeting other diseases have also been developed including a purinergic receptor P2X7 antagonist [ 18 F]F-PTTP for the detection of inflammation [78] , [ 99m Tc]Tc-GlcNAc-PEI (N-acetylglucosamine (GlcNAc) conjugated polyethylenimine (PEI)) specifically interacts with desmin and vimentin expressed on activated hepatic stellate cells (HSCs) for assessing liver fibrosis [79] , [ 18 F] FPGal based on isotonicamide for the imaging of asialoglycoprotein receptor (ASGPR) related liver disease [80] , and [ 68 Ga]Ga-HZ20 for the quantitative analysis of angiotensin [81] converting enzyme 2 (ACE2) expression in novel coronavirus sensitive organs [81] . The representative tracers mentioned above are summarized in Table 2 . Since [ 177 Lu]Lu-DOTA-TATE was successively approved by European Medicines Agency (EMA) and FDA for the treatment of gastroenteropancreatic neuroendocrine tumors (GEP-NETs), and along with the positive results obtained from phase III clinical trial of [ 177 Lu]Lu-PSMA-617 developed by Novartis for the treatment of metastatic castrationresistant prostate cancer (mCRPC), 177 Lu-labeled radiopharmaceuticals has attracted increasing attention in radionuclide therapy. Zhu's group has carried out the clinical translational researches of [ 177 Lu]Lu-DOTA-EB-TATE, a radiolabeled somatostatin analog modified by Evans blue [83] . In addition, the group is also conducting a clinical study of [ 177 Lu] Lu-EB-PSMA. Radiolabeling, kit formulation, and animal biodistribution of [ 177 Lu]Lu-EDTMP and [ 177 Lu]Lu-DOTMP have been investigated [84, 85] . Shanghai Huashan Hospital conducted the first clinical study of 177 Lu-labeled radiopharmaceuticals in China which is [ 177 Lu]Lu-EDTMP for the pain palliation of bone metastases [86] . Ma et al. conducted radiolabeling study and preliminary biological evaluation of [ 177 Lu]Lu-Rituximab [87] . Liu's group developed a highly tumor-selective anti-PD-L1 (αPD-L1) antibody, and subsequent radioimmunotherapy with [ 177 Lu]Lu-αPD-L1 antibody showed that this 177 Lu-labeled antibody could successfully upregulate antitumor immunity in the tumor microenvironment and turn "cold" tumors "hot" for immunotherapy [88] . Liu et al. investigated 177 Lu-labeled panitumumab and cetuximab (conjugated with DOTA), and the results suggested that both 177 Lu-labeled antibodies were promising for targeted therapy of EGFR-positive tumors especially for those that are resistant to antibody-based immunotherapy [89] . Alpha particles have high linear energy transfer (LET) and moderate path length, giving them an effective range of less than 10 cell diameters, which means cancer cells can be significantly damaged while causing minimal toxicity to the surrounding healthy cells. This renders targeted alpha therapy significant advantages, and it thus has become the hotspot of nuclear medicine research [90] . Based on homemade 211 At, several research works on 211 At-labeled agents have been carried out. Using N-succinimidyl-5-(tributylstannyl)-3-pyridinecarboxylate (SPC) as a bi-functional linker [91] , a one-step method was used for the preparation of [ 211 At]At-SPC-VP2 peptide [92] . The following research suggests that [ 211 At]At-SPC-VP2 has good in vivo stability and shows potential for targeted cancer radiotherapy. First investigation of the possible use of 211 At-labeled octreotide as a potential alpha-radionuclide therapeutic agent for non-small cell lung cancer cell treatment was reported by Yu's group [93] . [ 211 At]At-SPC-octreotide was prepared by indirect method, and it demonstrates much more lethal effect than the control groups (PBS, octreotide, and free 211 At) and a radiation dose-dependent apoptosis-inducing ability. In recent years, along with the technological advancement in the research and development of radiopharmaceuticals, and also with the introduction of NMPA's policy to encourage new drug creation, a lot of domestic and foreign radiopharmaceutical companies have been stepping up efforts on radiopharmaceuticals registration application in China. A batch of new radiopharmaceuticals have entered either the approval process or the clinical trials or marketing approval stage, and some of these radiopharmaceuticals are expected to be approved and serve the patients clinically in the near future. The current status of radiopharmaceutical application and approval by the NMPA in China is listed in Table 3 . In the past 10 years, major progress has been made in the research and development of diagnostic and therapeutic pharmaceuticals for cancer, cardiovascular system and central nervous system diseases, immunotherapy inflammation, and infection. Some radiopharmaceuticals are in the stage of clinical translation or marketing authorization. However, the radiopharmaceuticals currently in clinical application in China are mainly generic drugs, and the gap compared with developed countries is still quite significant, especially in the area of research and development and clinical translation of therapeutic radiopharmaceuticals. Proceeding from the actual situation in China, the important future trends may be including the following aspects: (1) production of medical radionuclides using both reactors and accelerators; (2) development of new targeted radiopharmaceuticals; and (3) improvement of radiopharmaceuticals supervision. In order to meet the basic requirements of the development of diagnostic and therapeutic radiopharmaceuticals, the production of the most important medical radionuclides such as 99 Mo, 131 I, 177 Lu, and 123 I needs to be emphasized in China. In addition, novel theranostic radionuclides pairs and alpha radionuclides such as 123/124 I, 64/67 Cu, 44/47 Sc, 68 Ge/ 68 Ga, 89 Zr, 211 At, 225 Ac, and 223 Ra need to be paid more attention. As an indispensable tool of molecular imaging, the future focus should be on the development of new positron radiopharmaceuticals including central nervous system receptorbinding radiopharmaceuticals with high affinity and selectivity and peptide-based imaging radiopharmaceuticals. The recent major advancements in solid-state detector technology have led to dramatic improvements of the sensitivity and spatial resolution of SPECT cameras with a concomitant sharp shortening of acquisition times. The SPECT imaging is still very active and can efficiently continue to complement PET diagnostic in routine clinical studies. Because of China's large size and uneven development of nuclear medicine, 99m Tc radiopharmaceuticals is expected to remain the mainstream of diagnostic radiopharmaceuticals for a long time, and thus, more new categories of 99m Tc radiopharmaceuticals need to be explored and developed. The theranostic radiopharmaceutical which is an integral part of nuclear medicine to achieve precision medicine will be a major future trend. The combination of 123 I /131 I radiopharmaceuticals already has found a well-recognized clinical application. By comparison, 68 Ga/ 177 Lu, 64 Cu/ 67 Cu, 44 Sc/ 47 Sc, and other radionuclide pairs and combinations, as well as a number of new targets, especially certain "broadspectrum" targets such as FAP and PSMA, have emerged as research focus in recent years. Many antibody based biotargets that have been clinically applied, such as PD-L1, CEA, MUC1, and HER2, also provide multiple options for the development of related radiopharmaceuticals, for example, the use of 89 Zr/ 64 Cu-labeled antibodies for radioimmunoimaging, and the use of 177 Lu/ 90 Y/ 131 I-labeled antibodies for radioimmunotherapy. Furthermore, attention should also be paid to the unique advantages and promising prospects of targeted alpha therapy. The development and clinical application of alpha radiopharmaceuticals such as 225 Ac-and 211 At-labeled radiopharmaceuticals should be promoted and advanced. The past few years have witnessed a great number of revisions and improvements in relevant laws and regulations to better accommodate the characteristics of radiopharmaceuticals. Still, more rules and regulations that are both applicable and feasible need to be introduced, and the evaluation mechanism for radiopharmaceuticals remains to be further improved so as to provide better policy guarantee to the clinical trials and industrialization of new radiopharmaceuticals. As stated above, the issuing of the Mid-and Long-term Development Plan (2021) (2022) (2023) (2024) (2025) (2026) (2027) (2028) (2029) (2030) (2031) (2032) (2033) (2034) (2035) for Medical Isotopes will promote the clinical application of radiopharmaceuticals, meanwhile, to advance the research and development of new radiopharmaceuticals. 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The manuscript represents valid work, and neither this manuscript nor one with substantially similar content under the same authorship has been published or is being considered for publication elsewhere. Ethics approval This article does not contain any studies with human participants or animals performed by any of the authors. The authors declare no competing interests.