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Review

Theranostic Radiopharmaceuticals of Somatostatin Receptors for Patients with Neuroendocrine Tumors: Agonists Versus Antagonists—A Systematic Review and Meta-Analysis

by
Qi Wang
1,
Damiano Librizzi
1,2,
Shamim Bagheri
1,
Ali Ebrahimifard
1,
Azimeh Hojjat Shamami
1,
Anja Rinke
3,
Friederike Eilsberger
1,
Markus Luster
1 and
Behrooz Hooshyar Yousefi
1,*
1
Department of Nuclear Medicine, School of Medicine, Philipps Universität Marburg, Baldingerstrasse, 35043 Marburg, Germany
2
Department of Nuclear Medicine, University Hospital OWL, Evangelisches Klinikum Bethel, 33617 Bielefeld, Germany
3
Division of Gastroenterology and Endocrinology, Department of Internal Medicine, School of Medicine, Philipps Universität Marburg, Baldingerstrasse, 35043 Marburg, Germany
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2025, 26(17), 8539; https://doi.org/10.3390/ijms26178539
Submission received: 25 June 2025 / Revised: 14 August 2025 / Accepted: 22 August 2025 / Published: 2 September 2025
(This article belongs to the Special Issue Neuroendocrine Tumors: From Molecular Pathology to Novel Therapeutic Approaches, Including Theranostics)
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Abstract

Neuroendocrine tumors (NETs) are a rare and heterogeneous class of neoplastic lesions, but their prevalence has increased significantly over the past three decades. These tumors are aggressive and difficult to treat. Improving diagnostic efficiency and treatment effectiveness is important for patients with neuroendocrine tumors. Radiopharmaceutical therapeutic diagnostics combines diagnosis and treatment technology and has broad prospects in precision medicine, especially for the early diagnosis and treatment of tumors. To compare the diagnostic advantages of radiolabeled somatostatin receptor agonists and antagonists for liver metastases from NETs and the disease control rate in NET patients. Systematic search of PubMed, Embase, Cochrane, Ovid, Scopus, and Web of Science databases up to 29 October 2024. Clinical trials of somatostatin receptor agonists and antagonists for NET diagnosis or treatment. Following PRISMA guidelines, data were independently extracted by two researchers. Pooled diagnostic or treatment effects and 95% CIs were reported using a random-effects meta-analysis model. Effect of somatostatin receptor agonists and antagonists in detecting liver metastases and disease control rate. Risk Ratio (RR) for liver metastasis detection and Effect Size (ES) for disease control rate were calculated. From 5291 articles, 52 were included in the meta-analysis. Radiolabeled somatostatin receptor antagonists were significantly more effective than agonists in detecting liver lesions (RR = 11.57, 95% CI: 4.10, 32.67). Disease control rates were higher with antagonists (ES = 0.90, 95% CI: 0.83, 0.96) compared to agonists (ES = 0.82, 95% CI: 0.78, 0.85, z = 2.12, p = 0.03). Radiolabeled somatostatin receptor antagonists outperform agonists in diagnosing hepatic lesions and controlling disease in NETs, highlighting their clinical superiority. This meta-analysis provides critical insights into the diagnostic and therapeutic efficacy of somatostatin receptor antagonists, and may offer a potential paradigm shift in the management of neuroendocrine tumors. Nevertheless, the smaller number of studies on antagonists may limit the generalizability of the findings and underscore the need for further clinical trials to validate these results.

1. Introduction

Neuroendocrine neoplasms (NENs) are a rare and diverse group of neoplasms originating from neuroendocrine cells throughout the body. The gastroenteropancreatic region is the most common site of origin for these tumors. The hormonal secretions of these neoplasms result in a wide spectrum of symptoms, contingent upon the tumor’s anatomic location and the specific hormone it produces [1,2,3]. NENs are classified as neuroendocrine tumors (NETs) or neuroendocrine carcinomas (NECs) depending on tumor grade, which is based on the proliferation rate, and the degree of differentiation, which is how similar the tumor is to normal cells. NETs range from inert to moderately aggressive, whereas NECs are highly aggressive. Highly differentiated NETs are classified into three categories based on mitotic rate and Ki-67 index: low-grade (G1), intermediate-grade (G2), and high-grade (G3). High-grade (G3) NETs are more aggressive than low-grade (G1) NETs. Some tumors have different levels of differentiation, called mixed neuroendocrine-nonneuroendocrine tumors [4,5]. In addition to their histological traits and anatomic sites, neuroendocrine tumors (NETs) can also be classified as functional, with these neoplasms eliciting corresponding clinical manifestations through the secretion of various biologically active compounds. Despite their relative rarity, NETs have demonstrated a notable increase in incidence over recent decades. This increase can be partially attributed to enhanced awareness and diagnostic techniques. In contrast to other types of epithelial malignancies, neuroendocrine tumors (NETs) generally appear inert; however, they may also demonstrate malignant potential, particularly when they arise in the lungs, digestive tract, and pancreas [6,7,8,9].
NETs are diagnosed and monitored through a multifaceted and comprehensive evaluation process. This process includes clinical symptoms, biochemical markers (e.g., chromogranin A, urinary 5-hydroxyindoleacetic acid, neuron-specific enolase, pancreatic polypeptides, etc.) [10], histopathology, and imaging (e.g., anatomical imaging (CT, MRI, etc.).); functional imaging ([68Ga]Ga-DOTA-SSA PET/CT/MRI and [18F]F-FDG PET/CT); and molecular genetic testing (testing for mutations such as MEN1 and TP53). These tools, along with emerging technologies like NETest and liquid biopsies (testing for circulating tumor DNA and microRNA), improve diagnostic accuracy and disease monitoring efficiency as well as precision medicine in the treatment of NENs [11,12,13].
The treatment of NETs is individualized according to the biology of the tumor and is flexible depending on the biology of the tumor and the extent of the lesion. However, for resectable disease, the first recommended procedure is resection with regional lymph node dissection. For biologically abnormal disease, neoadjuvant chemotherapy may be performed on a case-by-case basis. Somatostatin Analogues are recommended for patients who are SSR-positive or have hormonal symptoms. Other recommended treatments include peptide receptor radionuclide therapy (PRRT), targeted therapy, immunotherapy, chemotherapy, and liver-directed therapy. Palliative radiotherapy is recommended for patients with symptomatic bone metastases [4]. In recent years, PRRT has rapidly evolved into a more precise and highly targeted treatment modality. Remarkable potential has been shown by targeted radiation therapy, both in terms of efficacy and safety [14].
Somatostatins represent a class of peptide hormones that exist in two natural forms: somatostatin-14 (comprising 14 amino acids) and somatostatin-28 (comprising 28 amino acids). These hormones exhibit a high affinity for five specific subtypes of the somatostatin receptor (SSTR1, SSTR2, SSTR3, SSTR4, and SSTR5) [15]. The expression levels of these receptors vary significantly between normal physiological tissues and tumor samples, with higher levels of expression observed in tumors. The high expression levels of somatostatin receptors in tumors have led to the development of radiolabeled somatostatin receptor-based treatments and diagnostic methods for the management and evaluation of tumors [16,17]. The utilization of diagnostic and therapeutic radiopharmaceuticals (a pharmaceutical containing a radioactive isotope (radionuclide)), which are based on somatostatin receptor agonists, has been extensively promoted in clinical practice for the treatment of neuroendocrine tumors. These radiopharmaceuticals have been shown to exert a pivotal role in enhancing patient prognosis and quality of life [18,19,20,21,22,23]. A critical consideration in the application of agonists (compounds that bind to a receptor and activate it) for the management of neuroendocrine tumors pertains to their capacity for effective internalization within the tumor cells. Upon high-affinity binding to the receptor, agonists typically induce internalization of the ligand-receptor complex and promote accumulation of radiolabel. This process contributes to an efficient radiotherapeutic effect inside tumor cells while enhancing the intensity of the imaging signal, thus improving diagnostic and therapeutic accuracy [16,24,25]. Recently introduced SSTR antagonists, such as [68Ga]Ga-DOTA-JR11 [26], have made significant advances in the field of SSTR targeting. Preclinical and clinical studies have demonstrated that radiolabeled SSTR antagonists exhibit superior pharmacokinetics and tumor-to-background ratios (TBR) compared to somatostatin analogs (SSA) [27]. This enhanced performance may be attributed to their higher affinity for SSTR, despite the absence of internalization induction capacity in antagonists. Contrary to agonists, antagonists (compounds that bind to receptor but block or dampen the biological response that would normally be triggered by an agonist) do not promote internalization, and they bind to both the activated and inactivated conformations of SSTR, resulting in a slower dissociation rate compared to agonists. Consequently, the accumulation of radiolabel on the tumor cell surface is more intense compared to agonists. Furthermore, SSTR antagonists have a prolonged duration of action and enhanced stability in hydrophobic environments due to their enhanced chemical stability and hydrophobicity. In conclusion, SSTR antagonists exhibit excellent pharmacokinetic properties and better tumor visualization (Figure 1 and Figure 2) [28,29,30].
In this meta-analysis, we aimed to compare the diagnostic advantages of radiolabeled somatostatin receptor agonists and antagonists for liver metastases from neuroendocrine tumors and the disease control rate in patients with neuroendocrine tumors.

2. Materials and Methods

Systematic reviews and meta-analyses were conducted in accordance with the guidelines set forth by the Cochrane Collaboration, and the results were reported in adherence to the PRISMA (Preferred Reporting Items for Systematic Evaluations and Meta-Analyses) reporting guidelines. The meta-analysis was registered in the International Register of Protocols for Systematic Evaluation and Meta-Analysis (INPLASY2024120022). As this study did not involve human participants, no institutional review board approval or informed consent was required.
A systematic search of the PubMed, Embase, Cochrane, Ovid, Scopus, and Web of Science databases was conducted from inception to 29 October 2024. The search terms are detailed in Table A1. Following the removal of duplicates, two reviewers undertook a screening of the titles and abstracts. Additionally, the reference lists of the included studies and other published meta-analyses were reviewed. The full texts of the articles were evaluated independently by two reviewers, and the literature was screened in accordance with predefined criteria. Any discrepancies were resolved through negotiation. In the event that consensus could not be reached through discussion, a third reviewer was consulted to determine a resolution. Studies were considered eligible if they met the following criteria: (1) patients 18 years of age or older with neuroendocrine tumors; (2) radiolabeled somatostatin receptor agonists or antagonists; (3) diagnostic or therapeutic studies; (4) assessment of the disease control rate according to the RECIST1.1 criteria; (5) assessment of diagnostic efficacy for liver metastases; (6) patient-based studies; (7) non-combination therapy. Two authors independently extracted data using a standardized, predefined data collection form. Inconsistencies in the data were compared and combined into a final dataset that was independently checked by two additional reviewers. Articles were excluded if the patients in the study had tumors other than neuroendocrine tumors or if the extracted data were not suitable for meta-analysis. Non-English studies were also excluded. The outcome metrics were to compare the detection advantage of liver metastases and disease control rate in neuroendocrine tumors by radiotracer somatostatin receptor agonists versus antagonists. Weighted combined treatment effects were calculated using a random effects model. The variability between studies due to heterogeneity was estimated using the I2 statistic, with values greater than 50% indicating significant heterogeneity. Publication bias was comprehensively assessed using funnel plots, the Begg’s test, and the Egger’s test. Data analysis was performed with STATA 18 (StataCorp LLC, College Station, TX, USA).

3. Results

We ultimately collected 5291 papers, resulting in the final inclusion of 52 papers that could be used for meta-analysis (please see Figure 3 for the literature screening process). Among these, 4 articles were head-to-head comparisons of antagonists versus agonists effectiveness in detecting liver metastases in neuroendocrine tumors [31,32,33,34], 44 were used to pool agonist-treated neuroendocrine tumor disease control rates [35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78], and a further 4 articles were used to pool antagonist-treated neuroendocrine tumor disease control rates [30,79,80,81]. Four articles on diagnosis were tested for publication bias, and the results suggested that the funnel plot was asymmetric by Begg’s Test p = 0.462; meanwhile, Egger’s test p = 0.016, so we excluded the literature of Lin, Z. et al. [33] due to its unavailability. Finally, three articles were pooled and analyzed, and the pooled results of the funnel plot were symmetric (Figure A1), while Begg’s Test p = 0.734 and Egger’s Test p = 0.370. Regarding treatment, we did not find publication bias in the pooling of 44 studies of agonists for neuroendocrine tumors, with Begg’s Test p = 0.491 and Egger’s test p = 0.061, and the funnel plot was symmetrical (Figure A2). No publication bias was found after pooling the four studies of antagonists for neuroendocrine tumors, Begg’s Test p = 0.734, Egger’s test p = 0.494, and the funnel plot was symmetrical (Figure A3).

3.1. Diagnosis

In three articles included 4 head-to-head clinical trials (140 participants), with 4 antagonists and 1 agonist SST radiopharmaceuticals. The antagonists were significantly superior to agonists in the detection of liver metastases (RR = 11.57, 95% CI: 4.10–32.67) (Figure 4 and Table A2). There was no significant heterogeneity between studies (I2 = 0.0%, p = 0.966).

3.2. Therapy

A total of 44 agonist therapy trials with 2990 patients and 4 antagonist treatment trials with 109 patients were included. In the patient-based studies, the disease control rate was ES = 0.82 (95% CI: 0.78, 0.85), test of ES = 0: z = 47.49, p = 0.00, for agonist-treated NETs (Figure 5) (Table A3) and ES = 0.90 (95% CI: 0.83, 0.96), test of ES = 0: z = 21.23, p = 0.00, for antagonist-treated NETs (Figure 6) (Table A4). The Z-test showed that the antagonist outperformed the agonist in terms of outcome, with a Z-value = 2.12 and p = 0.03, indicating that the disease control rate of the antagonist (ES = 0.90) was significantly higher than that of the agonist (ES = 0.82). There was no significant heterogeneity between antagonist treatment trials (I2 = 6.98%, p = 0.36), whereas we demonstrated heterogeneity between agonist treatment trials (I2 = 77.06%, p = 0.00).

4. Discussion

To our knowledge, this is the first meta-analysis of somatostatin receptor agonists and antagonists for diagnosing and treating neuroendocrine tumors. Theranostics (also spelled theragnostics), which is a blend of therapy and diagnostics, is an important component of modern nuclear medicine. It enables precise diagnosis and treatment of tumors by identifying disease-specific characteristics, and integrates diagnosis and treatment using the same molecular targets, embodying the concept of ‘diagnostic and therapeutic integration’ [82].
The diagnostic and therapeutic management of neuroendocrine tumors should include monitoring clinical symptoms, assessing biochemical parameters, and performing routine and SSR imaging examinations [83]. Radiopharmaceuticals of SSTRs can achieve ‘integrated diagnosis and treatment’ and have broad application prospects for patients with advanced NETs [84]. [68Ga]Ga-DOTA-SSA has been shown to offer advantages over other diagnostic methods, particularly in patients with SSR-positive disease [85]. Somatostatin receptor radioligands have received sustained attention from a wide range of scientific researchers, greatly contributing to the development of peptide radiopharmaceuticals [86,87]. [68Ga]-based tracers, such as [68Ga]Ga-DOTA-TATE, are well-established and reliable. Additionally, [18F]-labeled SSR tracers, including [18F]F-SiFAlin-TATE, demonstrate significant potential. When PET/CT is unavailable, planar SSR scintigraphy ([111In]In-DTPA-octreotide scintigraphy), SPECT/CT ([99mTc]Tc-Tektrotyd SPECT/CT) or [123I-]I-MIBG scintigraphy as alternative methods, due to their lower spatial resolution and diagnostic accuracy, higher radiation dose, and longer procedure duration. SSR imaging is also important for pre-treatment assessment in patients with multiple metastatic tumors undergoing peptide receptor radionuclide therapy (PRRT) [83,88]. The NETTER-1 study demonstrated that PRRT is well-tolerated and effective for patients with unresectable or metastatic, well-differentiated NETs who have experienced tumor progression under SSA biological therapy [89]. Additionally, [18F]F-FDG-PET/CT may be beneficial for patients with NET G2 or G3. The role of CT and MRI scans should not be overlooked, as they are widely used and provide consistent results [83]. The application of somatostatin receptor radiopharmaceuticals in clinical practice has undoubtedly improved the diagnostic and therapeutic efficacy of patients with neuroendocrine tumors, as well as the quality of life and survival rate of patients [90,91]. Since antagonists can bind to more tumor targets than agonists, a paradigm shift in binding from internalizing SSTR2 agonists to antagonists is feasible [29,92,93]. Therefore, antagonists have a superior clinical indication.
Our study with three articles including 4 head-to-head clinical trials of agonists versus antagonists found that antagonists showed superior detection of hepatic metastatic compared with agonists in patient-based comparisons (RR = 11.57, 95% CI: 4.35, 32.67) and that this advantage may be due to antagonists having more binding sites at the SSTR receptor, as well as lower hepatic background uptake of antagonists compared to agonists in patients with neuroendocrine tumors. The majority of current antagonists have good clinical performance, especially in normal tissues where uptake is significantly lower than that of agonists. Krebs, S et al. [94] in a biodistribution and metrological analysis study of the antagonist [68Ga]Ga-DOTA-JR11 in patients with metastatic neuroendocrine tumors confirmed that the image contrast of liver lesions was significantly higher with [68Ga]Ga-DOTA-JR11 PET/CT compared to [68Ga]Ga-DOTA-TATE. They attributed this finding primarily to the fact that normal liver parenchyma has a much lower uptake on [68Ga]Ga-DOTA-JR11 PET/CT, making it easier to detect liver metastases. The liver represents a principal site of metastasis in patients with NETs [95], and the low background activity of the antagonist in the liver provides optimal image contrast. This capacity is of paramount importance not only for the diagnosis of NETs but also for the formulation of appropriate therapeutic strategies. The capacity to discern supplementary liver lesions through the utilization of antagonists may also result in a modification of the treatment plan when the prospect of localized treatment of liver metastases is contemplated. The performance of partial hepatectomy is questioned or even in instances where supplementary or bilobar liver lesions are identified [32,96].
In this analysis, 44 studies of radiolabeled somatostatin receptor agonists reported disease control rates for agonists in neuroendocrine tumors of ES = 0.82 (95% CI: 0.78, 0.85), z = 47.49, p = 0.00, and four studies of radiolabeled somatostatin receptor antagonists reported disease control rates for antagonists in neuroendocrine tumors of ES = 0.90 (95% CI: 0.83, 0.96), z = 21.23, p = 0.00. Comparison of the disease control rate of agonists and antagonists in neuroendocrine tumors by Z-test (z = 2.12, p = 0.03) showed that antagonists may be superior to agonists in the treatment of neuroendocrine tumors. SST2 receptor antagonists have favorable pharmacokinetic and biodistribution profiles, such as longer intratumoral residence time and higher tumor uptake, compared to agonists, and at the same time, antagonists have a higher tumor dose than agonists. In a preliminary clinical study of four patients with progressive NETs by Wild et al. [30], the tumor dose of the SSTR antagonist [177Lu]Lu-DOTA-JR11 was 1.7 to 10.6 times higher than that of the agonist [177Lu]Lu-DOTATATE. Despite the favorable results of clinical trials with antagonists, we cannot ignore the potentially toxic side effects, and in a study by Wild, D. et al. [81] on [177Lu]Lu-satoreotide tetraxetan, the radioactivity of radiopharmaceutical administered had to be reduced due to hematological toxicity.
A limitation of this study is the inclusion of a smaller number of scientific publications about antagonists, due to the fact that there are fewer clinical studies on the diagnosis and treatment using radiolabeled somatostatin receptor antagonists, which may have an impact on the generalizability of the conclusions. Furthermore, we included as many articles as possible on agonist treatment of neuroendocrine tumors in order to perform a comprehensive analysis. This resulted in considerable heterogeneity among the included studies, which may be attributed to the fact that the literature was included without specific limitations in terms of study design. In addition, the number of patients included in the respective studies and the duration of follow-up varied widely, as did the types of neuroendocrine tumors and the types of radiopharmaceuticals involved. However, despite the heterogeneity, the combined effect size was significantly different from zero (ES = 0: z = 47.49, p = 0.00), indicating a strong overall effect. The study by Wild D. et al. [30] in our analysis had only 4 patients. Although this study included only 4 patients, it provides the first clinical evidence that radiolabeled SST antagonists were superior to SST agonists in treating neuroendocrine tumors. Also, despite the small sample size, the results are in good accordance with other studies, suggesting that the conclusions drawn from this study are valid. It should be noted that this review did not include studies examining the use of PRRT in combination with chemotherapeutic agents for the treatment of neuroendocrine tumors. The articles by Huizing, D. M. V. et al. [53] and Kunikowska, J. et al. [54] both evaluated DCR at two time points. To avoid data duplication, we only included the DCR results with a longer follow-up time in our study. Additionally, studies of retreatment with PRRT (R-PRRT) after PRRT or re-retreatment with PRRT (RR-PRRT) after R-PRRT were not included. Several articles utilizing actinium-225 were also excluded on the grounds that alpha-particle rays are considered to be more distinct from beta particles.

5. Conclusions

The present study found that radiolabeled somatostatin receptor antagonists show significant advantages over agonists in detecting liver metastases and controlling disease in neuroendocrine tumor patients. The meta-analysis found that antagonists were significantly more effective in detecting liver lesions (RR = 11.57, 95% CI: 4.10, 32.67). Moreover, it had higher disease control rates (antagonist ES = 0.90, 95% CI: 0.83, 0.96) compared to agonists (agonist ES = 0.82, 95% CI: 0.78, 0.85), the z-value was 2.12, and the p-value was 0.03. This meta-analysis provides critical insights into the diagnostic and therapeutic efficacy of somatostatin receptor antagonists, and may offer a potential paradigm shift in the management of neuroendocrine tumors.
These findings highlight the potential of antagonists to improve diagnostic efficiency and treatment outcomes, emphasizing the importance of further research in this area to enhance patient care in NETs. Nevertheless, the smaller number of studies on antagonists may limit the generalizability of the findings and underscore the need for further clinical trials to validate these results.

Author Contributions

Conceptualization, B.H.Y. and D.L.; methodology, B.H.Y. and D.L.; software, Q.W.; validation, Q.W., A.E. and S.B.; formal analysis, Q.W. and A.H.S.; investigation, Q.W., S.B. and A.H.S.; resources, M.L.; data curation, B.H.Y., Q.W. and D.L.; writing—original draft preparation, Q.W., B.H.Y. and D.L.; writing—review and editing, B.H.Y., D.L., M.L., A.R. and F.E.; visualization, Q.W.; supervision, M.L., B.H.Y. and D.L.; project administration, B.H.Y., D.L. and M.L.; funding acquisition, M.L. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

All data are included in the article. If further information is required, please contact the corresponding author.

Acknowledgments

The research is supported by the Department of Nuclear Medicine, School of Medicine, Philipps University Marburg. Figure 1 and Figure 2 were created using Biorender (BioRender Inc., Toronto, ON, Canada; available at https://biorender.com accessed on 25 June 2025), and we have obtained the confirmation of publication and licensing rights (Figure 1 agreement number: DB27DFVKVI and Figure 2 agreement number: KI27AH0TDL). The original chemical structure in Figure 2 came from Molview v2.4.6, (Herman Bergwerf, The Netherlands, available at: https://molview.org accessed on 25 June 2025).

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

NENsNeuroendocrine neoplasms
NETsNeuroendocrine tumors
NECsNeuroendocrine carcinomas
RRRisk Ratio
ESEffect Size
SSTRSatostatin Receptor
PRRTPeptide receptor radionuclide therapy
PRISMAPreferred Reporting Items for Systematic Evaluations and Meta-Analyses
TBRTumor-to-Background Ratios
SSASomatostatin Analogs
MRMinor Response
CRComplete Response
PRPartial Response
SDStable Disease
DCRDisease Control Rate
MHMantel-Haenszel model

Appendix A

Table A1. Literature search strategy (taking PubMed as an example).
Table A1. Literature search strategy (taking PubMed as an example).
((((“Neuroendocrine Tumors”[Mesh]) OR (((((Neuroendocrine Tumor[Title/Abstract]) OR (Tumor, Neuroendocrine[Title/Abstract])) OR (Tumors, Neuroendocrine[Title/Abstract])) OR (NETs[Title/Abstract])) OR (NET[Title/Abstract]))) AND ((“Receptors, Somatostatin”[Mesh]) OR ((((((Somatostatin Receptor[Title/Abstract]) OR (Receptor, Somatostatin[Title/Abstract])) OR (Somatostatin Receptors[Title/Abstract])) OR (Receptors, Somatotropin Release Inhibiting Hormone[Title/Abstract])) OR (Receptors, SRIH[Title/Abstract])) OR (SRIH Receptors[Title/Abstract])))) AND ((((((((((“agonists” [Subheading]) OR (“antagonists and inhibitors” [Subheading])) OR (((antagonists[Title/Abstract]AND inhibitors[Title/Abstract]) OR (antagonists[Title/Abstract])) OR (inhibitors[Title/Abstract]))) OR ((“gallium Ga 68 DOTATATE” [Supplementary Concept]) OR ((((((((((((((DOTATATE gallium ga-68[Title/Abstract]) OR (gallium 68 DOTA-octreotide[Title/Abstract])) OR (gallium (68ga) dota-tate[Title/Abstract])) OR (gallium-dota-octreotate, ga-68[Title/Abstract])) OR (gallium DOTATATE, ga-68[Title/Abstract])) OR (gallium 68 DOTATATE[Title/Abstract])) OR (68Ga-DOTATATE[Title/Abstract])) OR (68gallium-DOTA-Tyr(3)-Thr(8)-octreotate[Title/Abstract])) OR (edotreotide gallium ga-68[Title/Abstract])) OR (gallium ga-68 edotreotide[Title/Abstract])) OR (gallium edotreotide ga-68[Title/Abstract])) OR (gallium ga 68-dotatoc[Title/Abstract])) OR (Ga-68 dota0-tyr3-octreotide[Title/Abstract])) OR (gallium Ga 68-edotreotide[Title/Abstract])))) OR ((“68Ga-DOTANOC” [Supplementary Concept]) OR (68Ga-DOTA-NOC[Title/Abstract]))) OR ((“Ga(III)-DOTATOC” [Supplementary Concept]) OR (((67Ga-DOTATOC[Title/Abstract]) OR (gallium-68 DOTATOC[Title/Abstract])) OR (68Ga-DOTATOC[Title/Abstract])))) OR ((“lutetium Lu 177 DOTATATE” [Supplementary Concept]) OR ((((((((177lutetium-DOTA-O-Tyr3-octreotate[Title/Abstract]) OR (lutetium 177Lu oxodotreotide[Title/Abstract])) OR (Lu-177 DOTATE[Title/Abstract])) OR (177Lu-DOTAOTyr3-octreotate[Title/Abstract])) OR (DOTATATE-177Lu[Title/Abstract])) OR (177Lu-DOTATATE[Title/Abstract])) OR (lutetium oxodotreotide Lu-177[Title/Abstract])) OR (Lutathera[Title/Abstract])))) OR ((“177Lu-octreotide, DOTA(0)-Tyr(3)-” [Supplementary Concept]) OR ((177Lu-octreotide, DOTA0, tyrosyl3-[Title/Abstract]) OR (177Lu-DOTATOC[Title/Abstract])))) OR ((((((68Ga-DOTA-JR11[Title/Abstract]) OR (18F-AlF-NOTA-LM3[Title/Abstract])) OR (68Ga-OPS202[Title/Abstract])) OR (68Ga-NODAGA-JR11[Title/Abstract])) OR (111In-DTPA-octreotide[Title/Abstract])) OR (68Ga-DATA(5m)-LM4[Title/Abstract]))) OR (((((177Lu-DOTA-JR11[Title/Abstract]) OR (177Lu-DOTA-LM3[Title/Abstract])) OR (tetulomab tetraxetan lu-177[Title/Abstract])) OR (177LU-DOTA-HH1[Title/Abstract])) OR (177Lu-Satoreotide Tetraxetan[Title/Abstract])))) AND ((((Theranostics[Title/Abstract]) OR (Theranostic[Title/Abstract])) OR ((“Therapeutics”[Mesh]) OR (((((Therapeutic[Title/Abstract]) OR (Therapy[Title/Abstract])) OR (Therapies[Title/Abstract])) OR (Treatment[Title/Abstract])) OR (Treatments[Title/Abstract])))) OR ((“Diagnosis”[Mesh]) OR ((((((((((((((Diagnoses[Title/Abstract]) OR (Diagnose[Title/Abstract])) OR (Diagnoses[Title/Abstract]AND Examinations[Title/Abstract])) OR (Diagnoses[Title/Abstract]AND Examination[Title/Abstract])) OR (Examination[Title/Abstract]AND Diagnoses[Title/Abstract])) OR (Examinations[Title/Abstract]AND Diagnoses[Title/Abstract])) OR (Antemortem Diagnosis[Title/Abstract])) OR (Antemortem Diagnoses[Title/Abstract])) OR (Diagnoses, Antemortem[Title/Abstract])) OR (Diagnosis, Antemortem[Title/Abstract])) OR (Postmortem Diagnosis[Title/Abstract])) OR (Diagnoses, Postmortem[Title/Abstract])) OR (Diagnosis, Postmortem[Title/Abstract])) OR (Postmortem Diagnoses[Title/Abstract]))))
Table A2. Head-to-head comparison of the detection rate of liver metastases between radiolabeled somatostatin receptor agonists and antagonists in patients with neuroendocrine tumors.
Table A2. Head-to-head comparison of the detection rate of liver metastases between radiolabeled somatostatin receptor agonists and antagonists in patients with neuroendocrine tumors.
StudyYearCountryNeuroendocrine Tumor TypesEvent_Exp 1Total_Exp 2Radiopharmaceuticals_ExpEvent_Ctrl 3Total_Ctrl 4Radiopharmaceuticals_Ctrl
Zhu, W.2020ChinaMetastatic, Well-Differentiated NETs1426[68Ga]Ga-DOTA-JR11126[68Ga]Ga-DOTATATE
Zhu, W. (1)2022ChinaWell-differentiated NETs816[68Ga]Ga-NODAGA-LM3016[68Ga]Ga-DOTATATE
Zhu, W. (2)2022ChinaWell-differentiated NETs816[68Ga]Ga-DOTA-LM3116[68Ga]Ga-DOTATATE
Liu, M.2024ChinaWell-differentiated NETs1012[18F]AlF-NOTA-LM3112[68Ga]Ga-DOTATATE
1 Event_Exp: The number of patients with more liver metastatic lesions detected with antagonists than with agonists. 2 Total_Exp: Number of all patients tested for antagonists. 3 Event_Ctrl: The number of patients with more liver metastatic lesions detected with agonists than with antagonists. 4 Total_Ctrl: Number of all patients tested for agonists.
Table A3. Disease control rates with radiolabeled somatostatin receptor agonists in patients with neuroendocrine tumors.
Table A3. Disease control rates with radiolabeled somatostatin receptor agonists in patients with neuroendocrine tumors.
StudyYearCountryEvent
(DCR = CR + PR + SD) ****		TotalNeuroendocrine Tumor TypesRadiopharmaceuticals
Grozinsky-Glasberg, S.2011Israel1010Malignant Gastrinomas[90Y]Y/[177Lu]Lu-DOTATOC
Vaisman, F.2015Brazil67Medullary Thyroid Cancer[177Lu]Lu-DOTATATE
Baum, R. P.2016Germany3756Gastroenteropancreatic and other NETs[177Lu]Lu-DOTATOC
Hörsch, D.2016Germany339357Gastroenteropancreatic, Bronchial, and other NETs[177Lu]Lu/[90Y]Y-DOTATOC/DOTATATE
Nilica, B.2016Austria4266Gastroenteropancreatic, Pulmonary, and other NETs[90Y]Y-DOTATOC/[177Lu]Lu-DOTATATE
Brabander, T. **2017Netherlands366443Gastroenteropancreatic and Bronchial NETs[177Lu]Lu-DOTATATE
Parghane, R. V. *2017India1319Pulmonary NETs[177Lu]Lu-DOTATATE
Thapa, P.2017India78Thymu, Mediastinum, Ureter, Esophagus, and Sacral NETs[177Lu]Lu-DOTATATE
Demirci, E.2018Turkey115160Bronchial, Pancreatic, Nonpancreatic Gastroenteropancreatic-NETs, Pheochromocytoma–Paraganglioma, and other NETs[177Lu]Lu-DOTATATE
Carlsen, Esben A.2019Europe91114Gastroenteropancreatic and other NETs[177Lu]Lu/[90Y]Y/[111In]In-DOTATOC/DOTATATE
Sharma, R.2019England4147Gastroenteropancreatic and other NETs[177Lu]Lu-DOTATATE
Zandee, Wouter T.2019Netherlands2834Pancreatic NETs[177Lu]Lu-DOTATATE
Adnan, A.2019India4359Gastroenteropancreatic, lung, other, and unknown[177Lu]Lu-DOTATATE
Beukhof, Carolien M.2019Netherlands410Medullary thyroid carcinoma (MTC)[177Lu]Lu-octreotate
Prasad, Vikas2020Europe, USA2223Gastroenteropancreatic and lung-NETs[177Lu]Lu-DOTATATE/DOTATOC
Satapathy, S.2020India3440Gastroenteropancreatic, lung, paraganglioma, MTC, and unknown[177Lu]Lu-DOTATATE
Graf, J.2020Germany4065Gastroenteropancreatic, pulmonary, and other NETs[177Lu]Lu-DOTATOC/[177Lu]Lu-DOTATATE
Hasan, O. K.2020Canada, Australia, Israel67Esthesioneuroblastoma[111In]In/[90Y]Y/[177Lu]Lu-octreotide
Huizing, D. M. V.2020Netherlands3139Gastroenteropancreatic and Pulmonary NETs[177Lu]Lu-DOTATATE
Kunikowska, J.2020Poland8192Gastroenteropancreatic, Pulmonary, and other NETs[90Y]Y/[177Lu]Lu-DOTATATE
Mirvis, E. 2020England2225Bronchial NETs[90Y]Y/[177Lu]Lu-DOTATATE
Parghane, R. V.2020India2743Medullary thyroid carcinoma[177Lu]Lu-DOTATATE
Pauwels, E.2020Europe2330Gastroenteropancreatic and other NETs[90Y]Y-DOTATOC
Thiis-Evensen, E.2020Norway6779Gastroenteropancreatic, pulmonary, and other NETs[177Lu]Lu-DOTA-octreotate
Zemczak, A.2020Poland6071Gastroenteropancreatic, Pulmonary, and other NETs[90Y]Y/[177Lu]Lu-DOTATATE
Parghane, R. V. *2021India69Paraganglioma[177Lu]Lu-DOTATATE
Severi, S.2021Italy3746Pheochromocytoma and Paraganglioma[90Y]Y-DOTATOC/[177Lu]Lu-DOTATATE
Sistani, G.2021Canada4047Gastroenteropancreatic, Pulmonary, and other NETs[177Lu]Lu-DOTATATE
Teker, F.2021Turkey2025Gastroenteropancreatic NETs[177Lu]Lu-DOTATATE
Zandee, Wouter T.2021Netherlands1722Midgut NETs[177Lu]Lu-DOTATATE
Almeamar, H.2022Ireland, Sweden, England4145Gastroenteropancreatic, Pulmonary, and other NETs[177Lu]Lu-DOTA-octreotate
Bongiovanni, A.2022Italy6265Gastroenteropancreatic, Pulmonary, and other NETs[177Lu]Lu-DOTATATE
Jiang, Y.Y.2022China, Singapore2327Gastroenteropancreatic, Paraganglioma, and otherNETs[177Lu]Lu-DOTA-EB-TATE PRRT
Metser, Ur.2022Canada3941Gastroenteropancreatic, Pulmonary, and other NETs[177Lu]Lu-DOTATATE
Raj, N.2022United States1318Gastroenteropancreatic, Pulmonary, and other NETs[177Lu]Lu-DOTATATE
Zidan, L.2022Australia, United States, Israel, England3540Pulmonary NETs[177Lu]Lu-DOTATATE
Sundlöv, A.2022Sweden5264Gastroenteropancreatic and other NETs[177Lu]Lu-DOTATATE
Hentzen, S.2023United States4552Gastroenteropancreatic NETs[177Lu]Lu-DOTATATE
Kepenek, F.2023Turkey1521Gastroenteropancreatic NETs[177Lu]Lu-DOTATATE
Liu, Q.2023Germany, China1425Medullary thyroid carcinoma[90Y]Y/[177Lu]Lu-DOTATATE/DOTATOC/DOTANOC
Mitjavila, M. 2023Spain381443Gastroenteropancreatic, Pheochromocytoma, Paraganglioma, Pronchopulmonary, and other NETs[177Lu]Lu-DOTATATE
Ryoo, H. G.2023Korea67Gastroenteropancreatic NETs[177Lu]Lu-DOTATATE
Iqbal, S.2024United States2325Gastroenteropancreatic and other NETs[177Lu]Lu-DOTATATE
Shin, Y. ***2024Korea4364Gastroenteropancreatic NETs[177Lu]Lu-DOTATATE
* Patients with Minor Response (MR) were included in the evaluation. ** 24 patients could not be evaluated. *** 2 patients could not be evaluated. **** Complete Response (CR): Disappearance of all target lesions. Non-target lesions must also resolve or normalize. Partial Response (PR): At least a 30% decrease in the SLD of target lesions. Stable Disease (SD): No significant shrinkage (≥30%) or growth (≥20%) of the target lesions. Disease Control Rate (DCR).
Table A4. Disease control rates with radiolabeled somatostatin receptor Antagonists in patients with neuroendocrine tumors.
Table A4. Disease control rates with radiolabeled somatostatin receptor Antagonists in patients with neuroendocrine tumors.
StudyYearCountryEvents (DCR = CR + PR + SD) *TotalNeuroendocrine Tumor TypesRadiopharmaceuticals
Wild, D.2014Switzerland, Germany, United States34Bladder, Pulmonary, and Ileum NETs[177Lu]Lu-DOTA-JR11
Reidy-Lagunes, D.2019United States, Germany1720Gastroenteropancreatic, Pulmonary, and Kidney NETs[177Lu]Lu-satoreotide tetraxetan
Baum, R. P.2021Germany, Singapore4047Gastroenteropancreatic, Pulmonary, and other NETs[177Lu]Lu-DOTA-LM3
Wild, D.2023Europe, Canada, Australia3638Gastroenteropancreatic, Pulmonary, Paraganglioma, Pheochromocytoma and other NETs[177Lu]Lu-satoreotide tetraxetan
* Complete Response (CR): Disappearance of all target lesions. Non-target lesions must also resolve or normalize. Partial Response (PR): At least a 30% decrease in the SLD of target lesions. Stable Disease (SD): No significant shrinkage (≥30%) or growth (≥20%) of the target lesions. Disease Control Rate (DCR).
Ijms 26 08539 g0a1
Figure A1. Head-to-head comparison of the detection rate of liver metastases between radiolabeled somatostatin receptor agonists and antagonists in patients with neuroendocrine tumors. The pooled results of the funnel plot. logrr: log risk ratio, se(logrr): standard error of the log risk ratio.
Figure A1. Head-to-head comparison of the detection rate of liver metastases between radiolabeled somatostatin receptor agonists and antagonists in patients with neuroendocrine tumors. The pooled results of the funnel plot. logrr: log risk ratio, se(logrr): standard error of the log risk ratio.
Ijms 26 08539 g0a1
Ijms 26 08539 g0a2
Figure A2. Disease control rates with radiolabeled somatostatin receptor agonists in patients with neuro-endocrine tumors. The pooled results of the funnel plot. ES: effect size, se (ES): standard error of the effect size.
Figure A2. Disease control rates with radiolabeled somatostatin receptor agonists in patients with neuro-endocrine tumors. The pooled results of the funnel plot. ES: effect size, se (ES): standard error of the effect size.
Ijms 26 08539 g0a2
Ijms 26 08539 g0a3
Figure A3. Disease control rates with radiolabeled somatostatin receptor Antagonists in patients with neuroendocrine tumors. The pooled results of the funnel plot. ES: effect size, se (ES): standard error of the effect size.
Figure A3. Disease control rates with radiolabeled somatostatin receptor Antagonists in patients with neuroendocrine tumors. The pooled results of the funnel plot. ES: effect size, se (ES): standard error of the effect size.
Ijms 26 08539 g0a3

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Figure 1. The utilization of radiolabeled Somatostatin Receptor (SSTR) agonists and antagonists has been demonstrated to facilitate imaging and therapeutic applications by binding to SSTR, a G-protein-coupled receptor that is overexpressed on neuroendocrine tumor cells. (a) The interaction of radiolabeled SSTR agonists with activated SSTR structures results in receptor internalization. (b) Radiolabeled SSTR antagonists interact with both activated and inactivated SSTR structures; however, they do not induce receptor internalization. The accumulation of radioactivity within tumor cells can be leveraged to generate imaging signals and enhance the efficacy of radiation therapy. Antagonists cause more radionuclides to accumulate on the surface of tumor cells, producing a stronger imaging signal and enhancing the effects of radiation therapy.
Figure 1. The utilization of radiolabeled Somatostatin Receptor (SSTR) agonists and antagonists has been demonstrated to facilitate imaging and therapeutic applications by binding to SSTR, a G-protein-coupled receptor that is overexpressed on neuroendocrine tumor cells. (a) The interaction of radiolabeled SSTR agonists with activated SSTR structures results in receptor internalization. (b) Radiolabeled SSTR antagonists interact with both activated and inactivated SSTR structures; however, they do not induce receptor internalization. The accumulation of radioactivity within tumor cells can be leveraged to generate imaging signals and enhance the efficacy of radiation therapy. Antagonists cause more radionuclides to accumulate on the surface of tumor cells, producing a stronger imaging signal and enhancing the effects of radiation therapy.
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Figure 2. Examples are provided for the development of agonist and antagonist radiopharmaceuticals for diagnostic and therapeutic use, based on somatostatin receptors, and their evolution. Also provided are the chemical structures of the compounds.
Figure 2. Examples are provided for the development of agonist and antagonist radiopharmaceuticals for diagnostic and therapeutic use, based on somatostatin receptors, and their evolution. Also provided are the chemical structures of the compounds.
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Figure 3. Literature screening flow chart.
Figure 3. Literature screening flow chart.
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Figure 4. Head-to-head comparison of the detection rate of liver metastases between radiolabeled somatostatin receptor agonists and antagonists in patients with neuroendocrine tumors. The pooled results were RR = 11.57, (95% CI: 4.10, 32.67) [31,32,34]. Note: RR is risk ratio, weights are from Mantel-Haenszel model (MH); continuity correction applied to studies with zero cells.
Figure 4. Head-to-head comparison of the detection rate of liver metastases between radiolabeled somatostatin receptor agonists and antagonists in patients with neuroendocrine tumors. The pooled results were RR = 11.57, (95% CI: 4.10, 32.67) [31,32,34]. Note: RR is risk ratio, weights are from Mantel-Haenszel model (MH); continuity correction applied to studies with zero cells.
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Figure 5. Disease control rates with radiolabeled somatostatin receptor agonists in patients with neuroendocrine tumors. The pooled result was ES = 0.82, (95% CI: 0.78, 0.85) [35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78].
Figure 5. Disease control rates with radiolabeled somatostatin receptor agonists in patients with neuroendocrine tumors. The pooled result was ES = 0.82, (95% CI: 0.78, 0.85) [35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78].
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Figure 6. Disease control rates with radiolabeled somatostatin receptor Antagonists in patients with neuroendocrine tumors. The pooled result was ES = 0.90, (95% CI: 0.83, 0.96) [30,79,80,81].
Figure 6. Disease control rates with radiolabeled somatostatin receptor Antagonists in patients with neuroendocrine tumors. The pooled result was ES = 0.90, (95% CI: 0.83, 0.96) [30,79,80,81].
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Wang, Q.; Librizzi, D.; Bagheri, S.; Ebrahimifard, A.; Hojjat Shamami, A.; Rinke, A.; Eilsberger, F.; Luster, M.; Hooshyar Yousefi, B. Theranostic Radiopharmaceuticals of Somatostatin Receptors for Patients with Neuroendocrine Tumors: Agonists Versus Antagonists—A Systematic Review and Meta-Analysis. Int. J. Mol. Sci. 2025, 26, 8539. https://doi.org/10.3390/ijms26178539

AMA Style

Wang Q, Librizzi D, Bagheri S, Ebrahimifard A, Hojjat Shamami A, Rinke A, Eilsberger F, Luster M, Hooshyar Yousefi B. Theranostic Radiopharmaceuticals of Somatostatin Receptors for Patients with Neuroendocrine Tumors: Agonists Versus Antagonists—A Systematic Review and Meta-Analysis. International Journal of Molecular Sciences. 2025; 26(17):8539. https://doi.org/10.3390/ijms26178539

Chicago/Turabian Style

Wang, Qi, Damiano Librizzi, Shamim Bagheri, Ali Ebrahimifard, Azimeh Hojjat Shamami, Anja Rinke, Friederike Eilsberger, Markus Luster, and Behrooz Hooshyar Yousefi. 2025. "Theranostic Radiopharmaceuticals of Somatostatin Receptors for Patients with Neuroendocrine Tumors: Agonists Versus Antagonists—A Systematic Review and Meta-Analysis" International Journal of Molecular Sciences 26, no. 17: 8539. https://doi.org/10.3390/ijms26178539

APA Style

Wang, Q., Librizzi, D., Bagheri, S., Ebrahimifard, A., Hojjat Shamami, A., Rinke, A., Eilsberger, F., Luster, M., & Hooshyar Yousefi, B. (2025). Theranostic Radiopharmaceuticals of Somatostatin Receptors for Patients with Neuroendocrine Tumors: Agonists Versus Antagonists—A Systematic Review and Meta-Analysis. International Journal of Molecular Sciences, 26(17), 8539. https://doi.org/10.3390/ijms26178539

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