This chapter provides an in-depth analysis of potential radiopharmaceuticals in clinical and preclinical studies, classified by different disease targets. We focus mainly on introducing targeted radiopharmaceuticals that have been evaluated in clinical trials or first-in-human studies (Table 4). The emerging disease targets related to radiopharmaceuticals that are potential to achieve clinical translation are also briefly introduced, although only preclinical studies are available. This chapter will cover an overview of the characteristics and functions of potential targets, the development of targeted radiopharmaceuticals, and their applications in clinical and preclinical studies. Furthermore, this study addresses current limitations and offers insights into the future direction of these potential radiopharmaceuticals (Fig. 4).

Widely studied targets for radiopharmaceuticals in tumour, neurodegenerative disorders and cardiovascular diseases. Radiopharmaceuticals are mainly used in the diagnosis and treatment of tumours, neurodegenerative disorders, and cardiovascular diseases. The TME contains tumour cells, immune cells, CAFs, and vascular endothelial cells, which play essential roles in cancer progression. Tumour targets for radiopharmaceutical development include GPCR-based transmembrane proteins (SSTR, GRPR, NTSR-1, CXCR4, and mGluR1), transmembrane proteins with four-pass domains (CLDN18.2), heterodimeric receptors (HER2 and the integrin family), other receptor (uPAR with no transmembrane and intracellular domains), immune checkpoints (PD-L1), and tumour antigens or other kinds of tumour biomarkers (PSMA, CD38, CAIX, GPC3, and Nectin-4). FAPs are expressed on both CAFs and tumour cells. VEGFRs are crucial tumour targets expressed by vascular endothelial cells. Immune cells that express checkpoints (PD-1, CTLA4, OX40, and ICOS), antigens (CD8, CD3, CD4, CD20, and CD30), and other biomarkers (IDO and Granzyme B) also serve as critical targets for cancer radiotheranostics. Aβ, tau, and α-synuclein plaques are the main causes of neurodegenerative disorders. The critical proteins expressed on synapses involved in neurotransmitter regulation include AMPAR and VMAT2 (transporter); FAAH and MAGL (signalling); SV2A, CB1R/21 R, sigma-1/2, and TSPO (transmembrane proteins), which have emerged as attractive targets for neurodegenerative disorders. Radiopharmaceuticals are currently used for the diagnosis of cardiovascular diseases. Owing to the important role of macrophages in disease progression, biomarkers that are expressed mainly on macrophages (TSPO, integrins) are potent imaging markers for cardiovascular pathology. Moreover, the FAP and VEGFR also showed potential in cardiovascular imaging. Part of this figure was created with Biorender.com

Tumour-targeted radiopharmaceuticals are emerging as promising clinical approaches that offer noninvasive, real-time diagnosis of tumour lesions and highly effective, safe treatments with strong antitumour efficacy.82 The identification of suitable targets facilitates successful clinical translation. In this section, we review the promising oncology targets and involved radiopharmaceuticals that exhibit significant clinical progress or remarkable cancer targeting capability. We will also discuss their potential applications, such as the use of tumour-specific targets in cardiovascular imaging, which is anticipated to reach clinical application in the future. Additionally, we summarize the pharmacological characteristics of these targets, and the current research and clinical progress on representative radiopharmaceuticals and provide an insight into their future development. We also present the chemical structures of clinically evaluated radiopharmaceuticals involving tumour-directed radiopharmaceutical targets (Figs. 5, 6).

Chemical structures of clinically evaluated tumour-direct FAP, PSMA, and SSTR targeting radiopharmaceuticals. Representative clinically evaluated tumour-directed FAP-, PSMA- and SSTR-targeting radiopharmaceuticals. PSMA-targeting radiopharmaceuticals with a glutamate-urea-lysine structural motif, including PSMA-11, PSMA-1007, PSMA-617, and rhPSMA-7.3, have been approved. PSMA-targeting ligands that enable simultaneous diagnosis and therapy, including PSMA-I&T and rhPSMA, are of high value. SSTR-targeting radiopharmaceuticals play essential roles in the radiotheranostics of NETs. The antagonists, including LM3 and JR11, which have greater safety and affinity, are promising in SSTR-targeting imaging agents. FAP-targeting radiotracers may prove advantageous over [18F]FDG in the localization and visualization of solid tumours, such as FAPI-04, FAPI-46, and FAPI-74. Additionally, FAP-2286 has been shown to facilitate radiotheranostics. Grey circles: natural amino acids; blue circles: unnatural amino acids; highlighting in red: labelling with fluorine-18; highlighting in purple: chelators for metal radionuclide labelling

Chemical structures of clinically evaluated tumour-direct Integrin, CXCR4, GRPR, UPAR, NTSR-1, Nectin-4 targeting radiopharmaceuticals. Representative clinically evaluated tumour-directed promising radiopharmaceuticals targeting Integrin, CXCR-4, GRPR, uPAR, NTSR-1, and Nectin-4. In the Integrin family, RGD motif-based αvβ3-targeting radiopharmaceuticals, particularly [99mTc]Tc-3PRGD2, may be the next widely implemented diagnostic agent in clinical applications. Integrin αvβ6 targeting ligand 5 G has also demonstrated promising results in clinical trials. The efficacy of CXCR4-targeting ligands, including pentixafor and pentixather, as well as uPAR-targeting ligand AE105, has been demonstrated in numerous clinical studies. GRPR antagonists based on the BBN-like peptides, such as BBN(7–14), RM2, AMTG, and NeoBOMB1, have demonstrated remarkable therapeutic efficacy in the RPT of GRPR-positive tumours. A non-peptide NTSR-1 antagonist, 3BP-227, has been demonstrated to exhibit great receptor affinity and diminished normal organ uptake, making it a promising NTSR-1-targeted radiopharmaceutical for clinical investigation and translation. The bicyclic-peptide-based radiotracer, [68Ga]Ga-N188, has been demonstrated to be efficient for imaging tumour Nectin-4. Grey circles: natural amino acids; blue circles: unnatural amino acids; highlighting in red: labelling with fluorine-18; highlighting in purple: chelators for metal radionuclide labelling

The tumour microenvironment (TME), which comprises tumour cells, cancer associated fibroblasts (CAFs), microvascular cells, immune cells and the extracellular matrix, plays a fundamental role in tumour progression, invasion and migration.83 FAP is a transmembranous subtype II serine protease. It is upregulated in 90% of CAFs in multiple cancers and is expressed at low levels in the fibroblasts of healthy adult tissues.84 The ability of FAP inhibitors (FAPIs) to target the TME is well-suited for the design and development of targeted radiopharmaceuticals.

FAP-targeting small molecule inhibitors have been studied in-depth in radiopharmaceutical clinical studies. Loktev et al. reported two FAPIs based on the quinoline structure: FAPI-01 for radioiodine labelling and its nonhalogenated derivative FAPI-02. In a patient with locally advanced lung adenocarcinoma, [68Ga]Ga-FAPI-02 showed greater metastatic lesion uptake and imaging contrast than did [18F]FDG. However, the short retention time of [68Ga]Ga-FAPI-02 limits its clinical applications.85 Subsequently, 13 novel FAPIs were designed for therapeutic applications by Lindner et al. Among these, FAPI-04 is considered the most valuable.86 On the basis of the PET/CT imaging results from 80 cancer patients, the tumour uptake of [68Ga]Ga-FAPI-04 is the most pronounced in patients with sarcoma, oesophageal cancer, breast cancer (BC), and cholangiocarcinoma (mean standardized uptake value [SUVmean]: 12 at 1 h after injection).87 Chen et al. performed a comprehensive comparative evaluation of [68Ga]Ga-FAPI-04 with [18F]FDG in 75 patients with different types of cancers and reported that [68Ga]Ga-FAPI-04 was more sensitive and accurate than [18F]FDG in detecting primary and metastatic lesions (detection rate of primary tumours: 98.2% vs. 82.1%; lymph nodes: 86.4% vs. 45.5%).88 To increase tumour uptake and prolong the retention time of FAPIs, Loktev et al. modified the structure of the quinoline molecule, the binding region between quinoline and the chelators and synthesized 15 new FAPIs.89 FAPI-46 has demonstrated superiority as a diagnostic agent in clinical imaging studies because of its low uptake in normal tissues. Ferdinandus et al. used [68Ga]Ga-FAPI-46 to detect 400 lesions in 69 patients and demonstrated its potential to differentiate between inflammatory and malignant uptake.90

Given the lower end-point positron energy and longer half-life, 18F-fluorinated FAPIs may be more appropriate for promoting the imaging modalities that benefit patients. [18F]FAPI-74 is a potential tracer that is absorbed by tumours and rapidly excreted by the kidneys. Xu et al. investigated the diagnostic performance of [18F]FAPI-74 in 112 patients with gastric, liver, and pancreatic cancer. Compared with [18F]FDG, [18F]FAPI-74 has advantages in detecting primary tumours, local recurrence, and bone and visceral metastases of cancer; however, in terms of specificity, [18F]FAPI-74 does not have a significant advantage over [18F]FDG.91

To meet the challenge of the limited retention time of radiolabelled FAPI within tumour cells, strategies aimed at modulating PK through increased binding ability with serum albumin have gained prominence. Two widely used albumin binders, namely, 4-(p-iodophenyl) butyric acid (IPBA) and truncated Evans blue (EB), have shown potential in enhancing the tumour accumulation and retention of radiopharmaceuticals, thereby reinforcing their therapeutic effects.92 Wen et al. developed a series of albumin-binding FAPIs based on FAPI-02, named EB-FAPI-B1 to B4. Among the four radiopharmaceuticals, [177Lu]Lu-EB-FAPI-B1 showed significant tumour uptake and prolonged retention time; moreover, it maintained high uptake even at 96 h post-injection.93 Fu et al. conducted a first-in-human and dose-escalation study of the EB-conjugated FAPI, [177Lu]Lu-EB-FAPI ([177Lu]Lu-LNC1004), in patients with metastatic radioiodine-refractory thyroid cancer. In these patients, the dose of 3.33 GBq per cycle was well tolerated, with encouraging therapeutic efficacy (objective response rate and disease control rate of 25% and 83%, respectively) and acceptable adverse effects.94 Meng et al. synthesized three albumin-binding FAPI ligands (FSDD0I, FSDD1I, and FSDD3I) derived from FAPI-04 by coupling IPBA with a bifunctional chelator. The authors showed that the binding affinity of these three FAPI ligands was not impaired after IPBA conjugation. PET/CT imaging demonstrated that [68Ga]Ga-FSDD0I had significant tumour uptake compared with [68Ga]Ga-FAPI-04. Notably, [68Ga]Ga-FSDD0I exhibited significantly greater tumour uptake and prolonged retention time than the other two tracers did, which might be attributed to its enhanced albumin-binding properties or relatively low hydrophilicity.95 In addition to conventional albumin binders, fatty acids, such as palmitic acid (C16), have been investigated as albumin-binding moieties. Zhang et al. conjugated lauric acid (C12) and C16 to FAPI-04 and reported that in comparative therapeutic assessments with [177Lu]Lu-FAPI-04, both [177Lu]Lu-FAPI-C12 and [177Lu]Lu-FAPI-C16 demonstrated superior therapeutic efficacy compared with [177Lu]Lu-FAPI-04; moreover, [177Lu]Lu-FAPI-C16 exhibited significantly prolonged tumour retention compared with [177Lu]Lu-FAPI-C12.96 Another effective method to resolve the issues of short tumour retention is to develop dimer derivatives. Zhao et al. synthesized a FAPI dimer, DOTA-2P(FAPI)2 based on FAPI-46. Clinical evaluations indicated that [68Ga]Ga-DOTA-2P(FAPI)2 exhibited prolonged tumour retention compared with the monomer, [68Ga]Ga-FAPI-46, with a sustained high concentration in the blood pool at four hours post-injection.97 In a recent retrospective study, Yadav et al. examined the clinical outcomes of FAPI dimer radionuclide therapy utilizing [177Lu]Lu-DOTAGA-FAPi in a cohort of 19 patients with metastatic BC. The promising clinical disease control rate was 95%, and the clinical objective response rate was 84%. Furthermore, no severe adverse effects, including haematological, renal, or hepatic toxicities, were observed during the study.98

Compared with the small-molecule FAPI series, cyclic peptide FAPIs have increased target selectivity, high binding affinity, and prolonged tumour retention time, thus demonstrating promising outcomes in clinical trials. In particular, 3B Pharmaceuticals reported a potential clinical candidate, FAP-2286 which was screened from 263 different FAP-targeting peptide structures. An initial clinical evaluation or recurrence detection in 64 patients with 15 cancer types revealed that the tumour uptake of [68Ga]Ga-FAP-2286 was much greater than that of [18F]FDG in primary tumours and lymph node metastases (median SUVmax: 11.1 and 10.6 vs. 6.9 and 6.2), and the primary tumour detection rate of [68Ga]Ga-FAP-2286 was significantly greater than that of [18F]FDG PET/CT (100% vs. 80.4%). Moreover, it could be considered the preferred alternative to [18F]FDG in cancers with low to moderate uptake.99 Recently, Liu et al. compared the performance of [18F]AlF-FAP-2286 with that of established radiopharmaceuticals in a preclinical study. [18F]AlF-FAP-2286 demonstrated superior imaging contrast with high target uptake and satisfactory retention in both mouse models and in cancer patients.100 Baum et al. reported the first-in-human results of [177Lu]Lu-FAP-2286 in 11 patients with advanced adenocarcinomas of the pancreas, breast, rectum, or ovary. The dosage of 5.8 ± 2.0 GBq was well tolerated, and the whole-body effective dose was 0.07 ± 0.02 Gy/GBq. The mean absorbed doses for the kidneys and red marrow were 1.0 ± 0.6 Gy/GBq and 0.05 ± 0.02 Gy/GBq, respectively. These findings suggest that [177Lu]Lu -FAP-2286 RPT is a promising approach for relatively few side effects.101 In 2022, Rao et al. reported that [177Lu]Lu-FAP-2286 was administered to a patient with systemic metastases from squamous cell carcinoma of the right lung. After 9 weeks of treatment with a single dose of 7.0 GBq, a significant decrease of tumour FAP expression in the patient was observed, as indicated by the PET/CT scans of [68Ga]Ga-FAP-2286. This encouraging finding highlights the importance of [177Lu]Lu-FAP-2286 as one of the most promising radiopharmaceuticals.102

Detection of FAP in myocardial tissue allows early identification of cardiac injury due to increased FAP expression in activated myocardial fibroblasts, and FAPI has been extensively explored clinically in cardiovascular diseases such as infarction, heart failure, tumour treatment-related cardiotoxicity, and cardiomyopathy.103 Zhang et al. performed [68Ga]Ga-FAPI-04 PET/MR on 26 patients with advanced cardiac infarction and reported that FAPI uptake was significantly greater in the left ventricular remodeling group. A high FAPI signal predicts adverse ventricular remodeling, and FAPI imaging is expected to become a new diagnostic approach for reflecting ventricular remodeling.104

Currently, the insufficient retention time of FAPIs in tumours does not meet the requirements of clinical practice. However, several strategies have been developed to overcome this limitation. Moreover, FAP-targeting cyclic peptide radiopharmaceuticals are more advantageous and have greater potential for cancer therapy. We believe that FAP-targeting radiopharmaceuticals will be the protagonists of the next radiopharmaceutical revolution and will gain immense popularity.

PSMA is a type II membrane glycoprotein first identified in prostate cancer cell lines. PSMA is overexpressed in more than 90% of malignant PCs, and its expression level increases significantly with the degree of malignancy. Moreover, the PSMA expression level in normal tissues is 100- to 1000-fold lower than that in PCs. The excellent biological properties of PSMA make it a key target for developing novel radiopharmaceuticals.105 Recently, PSMA-targeting radiopharmaceuticals have become the hallmark of RPT because of their superior clinical performance in the diagnosis and treatment of patients with advanced and metastatic CRPC.106

For diagnosis, [18F]PSMA-1007 and [68Ga]Ga-PSMA-11 were approved for the diagnosis of PCs, and a head-to-head comparative study demonstrated that [18F]PSMA-1007 and [68Ga]Ga-PSMA-11 could identify intermediate- or high-risk PCs. Notably, [18F]PSMA-1007 additionally detected low-grade lesions of limited clinical relevance and overcame several practical restrictions related to 68Ga-labelling PSMA-targeting tracers because of its longer half-life, excellent energetic properties, and non-urinary excretion properties.107 [99mTc]Tc-MIP-1404 is another prospective PSMA-targeting SPECT radiopharmaceutical. Schmidkonz et al. analyzed 93 patients with histologically proven cancer who underwent [99mTc]Tc-MIP-1404 SPECT/CT scans prior to therapy.108 The authors suggested that [99mTc]Tc-MIP-1404 could detect lymph nodes and bone metastases in a subset of previously untreated patients with PC. However, it is worth noting that liver accumulation of [99mTc]Tc-MIP-1404 is high, making it difficult to diagnose liver metastases. The successful clinical translation of diagnostic radiopharmaceuticals has promoted the pursuit of PSMA-targeting therapeutic radiopharmaceuticals; however, the in vivo therapeutic effectiveness of three abovementioned ligands is limited. The successful development of [177Lu]Lu-PSMA-617 and advancements in its clinical application demonstrated the therapeutic value of PSMA-targeting radiopharmaceuticals.49,109 Images acquired from [68Ga]Ga-PSMA-617 PET/CT between 2 and 3 h post-injection appeared to be optimal uptake and imaging contrast, however, this does not match well with the half-life of gallium-68. Therefore, the design of PSMA-targeting ligands that can meet both diagnostic and therapeutic requirements is an emerging trend in the development of PSMA-targeting radiopharmaceuticals.110 To address this, Weineisen et al. developed PSMA-I&T with DOTAGA as a chelator, which enabled rapid and high-yield radiolabelling with both gallium-68 and lutetium-177. [68Ga]Ga-PSMA I&T shows promise for high-quality PET/CT imaging of metastatic PCs, while its 177Lu-labelled counterpart has targeting and retention properties for endoradiotherapy.111 A clinical trial using [177Lu]Lu-PSMA-I&T in 56 patients with mCRPC revealed that 80.4% of patients presented a decrease in prostate-specific antigen (PSA) levels, whereas 58.9% of patients presented a greater than 50% reduction in pain severity. None of the patients reported clinically significant severe adverse events during hospitalization or at 28 months of follow-up.112

A novel series of radiohybrid (rh) PSMA-targeting ligands were recently developed by incorporating a silicon fluoride acceptor (SiFA) for fluorine-19/fluorine-18 isotope exchange radiolabelling and a chelator for complexation with a (radio)metal (lutetium-177, gallium-68, or actinium-225) and have shown promising prospects in clinical applications. The FDA-approved lead rhPSMA diagnostic radiopharmaceutical [18F]flotufolastat (18F-rhPSMA-7.3) demonstrated favourable biodistribution and diagnostic efficacy for N-staging and localization of biochemical relapse in patients with recently diagnosed and recurrent PCs.113 In a first validation of the radiohybrid technology for therapeutic applications, [177Lu]Lu-rhPSMA-7.3 demonstrated 2.8-fold and 4.7-fold increases in tumour uptake compared with [177Lu]Lu-PSMA I&T at 1 and 168 h after injection, respectively. Nevertheless, the average absorbed dose is also relatively high in different healthy organs. For example, [177Lu]Lu-rhPSMA-7.3 accumulates 2.3-fold more in the kidney and 2.2-fold more in the bone marrow than [177Lu]Lu-PSMA-I&T does, which raises concerns about side effects.114 Wurzer et al. developed a novel radiotracer, 177Lu-labelling rhPSMA-10.1, via the isomerization of 177Lu-labelling rhPSMA-7 and the substitution of DOTAGA with DOTA, to further improve the PK in normal organs while maintaining high tumour uptake comparable to that of [177Lu]Lu-rhPSMA-7.3.115 Dierks et al. reported that [177Lu]Lu-rhPSMA-10.1 was well tolerated and responded to PSA with durable radiological responses in all four patients evaluated.116 Formal clinical trials are currently in progress to assess its potential in a prospective setting (NCT05413850).

Copper-64 and copper-67 are promising groups of diagnostic and therapeutic radionuclides because of their chemical properties in terms of decay characteristics and half-life, which facilitate their use for sequential PET/CT imaging and radiotherapy via the same chelator. The macrobicyclic hexamine cage sarcophagine (sar) is an effective chelator that can form a kinetically inert and stable CuII complex. In 2019, Zia et al. reported two sar ligands tethered to single or double PSMA-targeting moieties. The monomeric formulation [64Cu]CuSarPSMA had a similar tumour uptake effect to that of [68Ga]Ga-PSMA-11, while the bivalent formulation [64Cu]CusarbisPSMA had significantly better tumour uptake and prolonged retention than the monomeric formulation.117 Furthermore, in 2021, McInnes et al. investigated the therapeutic potential of [67Cu]CuSarbisPSMA.118 The results showed that [67Cu]CuSarbisPSMA and [177Lu]Lu-PSMA-I&T exhibited similar tumour inhibitory effects and survival prolongation at equivalent doses; moreover, the shorter half-life of copper-67 than of lutetium-177 (61.9 h vs. 6.7 d) implies that dosing could be repeated over a shorter period, thus providing more control of fast-replicating tumours. [64Cu]CuSarbisPSMA and [67Cu]CuSarbisPSMA are being evaluated in a clinical trial for the detection and treatment of PSMA-positive mCRPC (NCT04868604).

Additionally, several patients with mCRPC failed to respond adequately to targeted β-radionuclide therapy ([177Lu]Lu-PSMA) or respond well initially but later develop resistance to this therapy. Therefore, α-particles are also potent for PSMA-targeting radiopharmaceuticals. Selcuk et al. reported their clinical study with [225Ac]Ac-PSMA treatment in patients with [177Lu]Lu-PSMA-refractory mCPRC, showing that [225Ac]Ac-PSMA therapy was effective and safe with manageable toxicity.119 This treatment has potential even in advanced mCRPC patients who have exhausted almost all current treatment options.

In terms of the future development of PSMA-targeting ligands, there is an emerging trend to design and develop PSMA-targeting ligands that enable diagnosis and therapy with the same ligand, which could avoid discontinuity in diagnostic integration and tumour uptake or PK differences owing to ligand replacement. On the other hand, attempting to incorporate more radionuclides into the development of PSMA-targeting radiopharmaceuticals is also an attractive strategy for the future. As a leading compound in targeted radionuclide diagnostics and therapeutics, PSMA-targeting radiopharmaceuticals will continue to be reinvented in the future.

SSTR is a cyclic neuropeptide containing 14 amino acid residues. There are more than five types of SSTRs, among which SSTR2 is the most common and abundant. The activity of SSTRs is mediated by interactions with G protein-coupled growth inhibitor receptors. The SSTR is also a pioneer target in the field of targeted radiopharmaceuticals and plays an essential role in the diagnosis, staging and treatment of NETs.120 NETs are a diverse group of neuronal and endocrine cell-derived malignancies; the majority of them are characterized by slow and indolent growth, leading to delayed diagnosis with approximately 50% of cases showing metastasis at the time of diagnosis.121

SSTR-targeting radiopharmaceuticals provide greater sensitivity and specificity than conventional modalities do and they are unignorable for NET patient radiotheranostics. SSTR-targeting RPTs have been widely implemented as front-line therapeutic options for metastatic/inoperable NETs. Currently, several types of SSTR agonists are attracting increasing interest in clinical and preclinical studies. [68Ga]Ga-DOTA-TATE, [68Ga]Ga-DOTA-TOC, and [68Ga]Ga-DOTA-NOC are commonly used radiopharmaceuticals in clinical practice.122,123 These three radiopharmaceuticals differ slightly in their structures and targeting capabilities, however, there is no clinically relevant difference for [68Ga]Ga-DOTA-TOC and [68Ga]Ga-DOTA-TATE in detecting NETs in patients.123 These radiopharmaceuticals are most frequently applied in PET/CT imaging for the diagnosis of NETs. The therapeutic agent [177Lu]Lu-DOTA-TATE led to significantly longer progression-free survival and a substantially improved response rate, thus opening a new clinical landscape for the first-line treatment of NETs.124 Notably, EB-conjugated [177Lu]Lu-DOTA-TATE also exhibited promising clinical efficacy. A study involving 32 patients with NETs who underwent multiple cycles of [177Lu]Lu-DOTA-EB-TATE therapy demonstrated that dose escalations of up to 3.97 GBq per cycle seem to be well tolerated and more effective than 1.17 GBq per cycle.125 Recently, they reported that an optimized long-acting somatostatin analogue-based radiopharmaceutical with linker substitution, [177Lu]Lu-LNC1010, was well-tolerated in patients with various types of NETs, resulting in an 83% disease control rate and a 42% overall response rate after two treatment cycles and 3.3 GBq per cycle was the most appropriate therapeutic dose for subsequent trials.126

More efforts have been reported to improve the properties of SSTR-targeting diagnostic and therapeutic radiopharmaceuticals. Owing to its long half-life and excellent energy properties, [18F]AlF-NOTA-octreotide is a new potential radiopharmaceutical with favourable properties because of its low background uptake, particularly in the liver, high PET/CT imaging quality and favourable lesion identification rates in NETs, similar to those of [68Ga]Ga-DOTA-TATE.127 Johnbeck et al. reported that [64Cu]Cu-DOTA-TATE had a significantly higher tumour detection rate than did [68Ga]Ga-DOTA-TOC in patients with NETs.128 A follow-up study revealed that more newly added true-positive lesions were detected by [64Cu]Cu-DOTA-TATE than by [68Ga]Ga-DOTA-TOC, which could be attributed to the shorter positron range of copper-64 than that of gallium-68. Notably, despite the success of [177Lu]Lu-DOTA-TATE in clinical applications, there is considerable scope to improve its safety and efficacy. 212Pb-targeted α-emission therapy is effective in further improving both of these aspects. Delpassand et al. reported that eight of ten patients who received all four cycles of [212Pb]Pb-DOTAM-TATE had a safe and promising clinical outcome (2.50 MBq/kg).129

Major progress in SSTR-targeting radiopharmaceuticals is the development of SSTR antagonists, which appear to engage more binding sites on the receptor with good PK properties and superior tumour imaging than SSTR agonists do. Cescato et al. reported 32 SSTR antagonist analogues and demonstrated that compound 3 and 31 had high SSTR2 binding affinity and selectivity.130 Based on the structure of compound 31, a phase I imaging study also demonstrated that [68Ga]Ga-NODAGA-JR11 had favourable PK and PET/CT imaging performance, with fast elimination from the blood, leading to low background accumulation, particularly in the liver and gastrointestinal tract.131 The effective dose of [68Ga]Ga-NODAGA-JR11 was similar to that of 68Ga-labelled SSTR agonists established clinically; and showed no obvious toxicity (NCT04897542). A recent PET/CT scan of four radiolabelled SSTR antagonists in 549 patients revealed that among [68Ga]Ga-NODAGA-LM3, [68Ga]Ga-DOTA-LM3, [68Ga]Ga-NODAGA-JR11 and [68Ga]Ga-DOTA-JR11, [68Ga]Ga-NODAGA-LM3 appeared to have the best imaging characteristics and deserves further clinical development because of its increased sensitivity and accuracy.132 Xie et al. reported that the quality analysis and excellent imaging performance of [18F]AlF-NOTA-JR11 for NETs were better than those of [68Ga]Ga-DOTA-TATE, especially in the patient’s digestive system with low background uptake, which allowed the detection of more SSTR-overexpressing lesions of the primary and metastatic regions with higher imaging contrast.133

The successful application of SSTR antagonist-based radiotracers indicated that 177Lu-labelling antagonists could be used instead of 177Lu-labelling agonists in RPT. In particular, a phase I study of [177Lu]Lu-DOTA-JR11 in well-differentiated NETs showed that [177Lu]Lu-DOTA-JR11 could deliver the required radiation levels to NETs with a superior tumour-to-normal organ dose ratio; however, in this trial, the primary treatment regimen produced more severe haematologic toxicity than the same dose of SSTR2 agonist did.134 Handula et al. conducted the first preliminary clinical evaluation of [225Ac]Ac-DOTA-JR11, showing that although both [225Ac]Ac-DOTA-JR11 and [177Lu]Lu-DOTA-JR11 exhibited comparable biodistribution patterns in vivo, [225Ac]Ac-DOTA-JR11 showed poor stability in PBS and mouse serum, and greater renal accumulation than did [177Lu]Lu-DOTA-JR11. Thus, further optimization of the PK of [225Ac]Ac-DOTA-JR11 is needed for safe and efficacious targeted α-particle therapy for NETs.135

Given their greater safety and affinity, multiple clinical studies have proven that the development and modification of SSTR-targeting antagonists are promising research directions for SSTR-targeting radiopharmaceuticals. Emerging radiopharmaceuticals, including somatostatin analogues labelled with fluorine-18 (to overcome the limitations imposed by 68Ga), actinium-225 and terbium-161 (to increase therapeutic efficacy), are also promising. In addition, the development of combination therapies and the exploration of new indications are critical directions for SSTR-targeting radiotherapy.

Integrins are members of the heterodimeric transmembrane glycoprotein family, which contains 18 distinct alpha subunits and eight beta subunits in mammals. Integrins transmit biomechanical signals across cells and their environment. The integrin receptor is a veteran useful target for radiopharmaceuticals. Integrin receptor expression differs widely between normal tissues and cancer tissues and is significantly correlated with cancer progression and metastasis.136 For example, integrins αvβ3 and αvβ6 are typically expressed at low or undetectable levels in most normal epithelial cells but are overexpressed in a wide range of tumours; this characteristic makes them suitable radiotheranostics targets of multiple cancers.137

Integrin αvβ3 is the most frequently studied integrin because it is a highly specific biomarker that plays an integral role in tumour metastasis and angiogenesis; therefore, PET/CT and SPECT/CT imaging targeting αvβ3 expression are very promising diagnostic strategies. The binding of αvβ3 to the vitronectin surface is mediated by the RGD (Arg-Gly-Asp) tripeptide, which acts as a core recognition motif. The earliest monomeric integrin-targeting PET tracer for use in clinical practice was [18F]galacto-RGD, an 18F-fluorinated RGD with added glycosylation, which was primarily used in gliomas imaging because of its lower uptake in normal brain tissue than [18F]FDG.138 Other derivates, including [18F]Fluciclatide and [18F]RGD-K5, subsequently appeared. However, the synthesis process of [18F]galactose-RGD and its derivates is complex and inefficient; therefore, they are not commercially available on a large scale.