Prostate cancer (PCa) represents the second most prevalent malignant neoplasm among men worldwide, constituting approximately 7.3% of all cancer cases and ranking as the fifth leading cause of cancer-related mortality in males (1). In China, the incidence of PCa has increased significantly, surpassing both bladder and kidney cancers to become the most common malignant tumor in the male urogenital system (2). The biological behavior of PCa varies considerably based on its malignancy grade, which directly influences treatment strategies and prognosis.

Early-stage PCa demonstrates excellent outcomes, with nearly 100% five-year survival rates through surgical intervention and androgen deprivation therapy. However, metastatic PCa presents a markedly different prognosis, with five-year survival rates ranging from 36 to 54% and a median survival time of approximately 42 months (3). Thus, early diagnosis and accurate grading of PCa are of great significance for formulating therapeutic strategies and improving prognosis. Currently, multiparametric magnetic resonance imaging (mpMRI) is the most widely utilized imaging technique for the diagnosis of PCa. mpMRI offers high-resolution soft tissue imaging, enabling a detailed assessment of the anatomical structure of the prostate, precise localization of primary PCa lesions, and visualization of the involvement of pelvic lymph nodes and bones. However, studies indicate that mpMRI exhibits a sensitivity of up to 96% in detecting PCa, whereas its specificity ranges from 36 to 58%, reflecting a relatively high false-positive rate (4, 5). At the same time, mpMRI’s inability to provide whole-body imaging in a single examination limits its utility for comprehensive staging (6). Bone scintigraphy (BS), a sensitive and cost-effective imaging modality for detecting PCa bone metastases, is constrained by limited specificity due to frequent false-positive findings caused by benign bone conditions (7). Therefore, the exploration of precise morphological and functional characterization is crucial for the clinical management of PCa.

Prostate-specific membrane antigen (PSMA), a Type II transmembrane glycoprotein predominantly expressed in prostatic tissues, demonstrates upregulated expression correlated with malignancy grade and metastatic progression (8). PSMA has emerged as a crucial target for both diagnostic imaging and radionuclide therapy in PCa. Extensive research has demonstrated the significant value of [68Ga]- and [18F]-labeled PSMA positron emission tomography/computed tomography (PET/CT) in diagnosis, treatment response evaluation, and patient follow-up (9–15). For instance, a systematic review published by Satapathy et al. (14) demonstrated the excellent sensitivity of [68Ga]Ga-PSMA-11 and [68Ga]Ga-PSMA-617 PET/CT for initial detection in patients with suspected PCa. Ergül et al. (15) demonstrated that [68Ga]Ga-PSMA-11 PET/CT is a highly effective imaging modality for the initial evaluation of newly diagnosed PCa, leading to significant changes in its staging compared to conventional imaging methods. In addition to the [68Ga]Ga-labeled PSMA radiotracers, Chikatamarla et al. (16) demonstrated comparable superior diagnostic accuracy for primary staging of PCa using [18F]F-labeled PSMA inhibitor ([18F]F-PSMA-1007) in their largest study. Notably, PSMA avidity exhibits a significant positive correlation with baseline serum total PSA levels and Gleason grade group classification, reinforcing its prognostic validity (10, 16). In addition, the maximum standardized uptake value (SUVmax) is the most commonly used semi-quantitative parameter in PET/CT, and a prospective study by Jiao et al. (17) demonstrated that the optimal SUVmax cut-off value for distinguishing clinically significant PCa from benign prostate disease was 5.30.

Despite these advantages, PET faces limitations in clinical applications due to the high costs associated with radiotracers and specialized equipment (18, 19). In contrast, single-photon emission computed tomography (SPECT)/CT is more globally accessible, providing a cost-effective alternative for PSMA-targeted imaging. Furthermore, recent advances in SPECT/CT fusion imaging, which provide both anatomical and functional information, have facilitated the development of single-photon-labeled PSMA tracers (20). In recent years, researchers have designed multiple [⁹⁹ᵐTc]-labeled PSMA-targeted molecules for PCa detection (21–24).

Among these, [⁹⁹ᵐTc]Tc-PSMA-I&S, a PSMA-targeted compound introduced by Robu et al. (25) in 2016, was initially developed for radioguided surgery. This radiotracer is characterized by slow systemic clearance, enabling prolonged retention in tumor cells. Over 21 h post-injection, the lesion-to-background contrast progressively increases, making it particularly suitable for intraoperative detection and excision of PSMA-positive lymph node metastases. This distinctive characteristic may provide superior lesion-to-background contrast in delayed imaging, thereby potentially offering diagnostic advantages over other SPECT-based PSMA tracers, including [⁹⁹ᵐTc]Tc-MIP-1404 and [⁹⁹ᵐTc]Tc-HYNIC-PSMA. Owing to its stable and reproducible labeling process, [⁹⁹ᵐTc]Tc-PSMA-I&S demonstrates potential for SPECT imaging (25). Furthermore, advancements in SPECT/CT image reconstruction algorithms, photon attenuation correction, and scatter correction techniques have significantly enhanced the clinical utility of quantitative SPECT/CT.

Therefore, this study aims to investigate the clinical utility of [⁹⁹ᵐTc]Tc-PSMA-I&S SPECT/CT in the diagnosis of PCa, prediction of tumor metastasis, and assessment of malignancy grade.

This study adhered to the guiding principles of the Declaration of Helsinki and was approved by the Ethics Committee of Panzhihua Central Hospital (approval number: zhszxyykyll-2022-002). However, due to the retrospective nature of the study, written informed consent was waived.

PCa is one of the most prevalent malignancies among men. Early diagnosis and accurate risk stratification are critical for optimizing therapeutic strategies and improving patient prognosis (27). PSMA-targeted PET imaging has emerged as the gold standard for prostate cancer imaging, enabling highly sensitive early detection of subcentimeter primary malignancies, precise lymph node staging and metastatic assessment, recurrence detection, and therapeutic response evaluation. PSMA PET imaging has been incorporated into major clinical management guidelines, including those of the National Comprehensive Cancer Network, the European Society for Medical Oncology, and the European Association of Urology (29–31). While PET/CT with [⁶⁸Ga]Ga-PSMA or [¹⁸F]F-PSMA tracers has demonstrated exceptional efficacy in primary PCa detection (32), its widespread clinical implementation is constrained by high operational costs. In contrast, SPECT/CT offers broader accessibility and cost-effectiveness, positioning it as a viable alternative for PSMA-targeted imaging. Among recently developed [⁹⁹ᵐTc]Tc-labeled PSMA probes, [⁹⁹ᵐTc]Tc-PSMA-I&S—originally designed for radioguided surgery—has emerged as a promising tracer for PCa imaging. Analyzed the application value of [⁹⁹ᵐTc]Tc-PSMA-I&S SPECT/CT in the diagnosis, metastasis prediction, and tumor invasion assessment of PCa.

Based on comprehensive analysis of image quality, clinical practicality, and patient compliance, we identified 4 h post-injection as the optimal imaging timepoint for [⁹⁹ᵐTc]Tc-PSMA-I&S. Biodistribution analysis revealed characteristic tracer uptake patterns: high uptake in bilateral parotid glands, submandibular glands, kidneys, and bladder; moderate uptake in the liver, spleen, and small intestine; and low uptake in the heart, lungs, thyroid, muscles, bones, and brain tissues. These findings indicate predominant tracer excretion via the urinary and hepatobiliary systems, with minimal physiological uptake in non-target tissues. The absence of adverse events further underscores the safety and stability of [⁹⁹ᵐTc]Tc-PSMA-I&S for clinical use.

In the present study, [⁹⁹ᵐTc]Tc-PSMA-I&S SPECT/CT exhibited excellent diagnostic performance for primary PCa, with sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 100, 77.28, 95.12, 100, and 95.83%, respectively. These results align with those reported by Farkas et al. (33), who demonstrated comparable diagnostic metrics (sensitivity 86%, specificity 100%, positive predictive value 100%, negative predictive value 83%, and accuracy 92%). Werner et al. (22) similarly demonstrated high sensitivity (92%) for [⁹⁹ᵐTc]Tc-PSMA-I&S SPECT/CT in detecting primary PCa. These findings are also consistent with previous studies by Wang et al. (34) and Goffin et al. (35), who reported detection rates of 100 and 94% for primary tumors in 31 and 104 PCa patients, respectively, using other [⁹⁹ᵐTc]Tc-labeled PSMA radiotracers (MIP-1404 and HYNIC-PSMA) for initial staging. Regarding PSMA-targeted PET tracers, Basha et al. (36) reported a detection rate of 96% using [68Ga]Ga-PSMA-11 PET/CT in 173 primary PCa patients. Collectively, these results underscore the promising potential and clinical utility of [⁹⁹ᵐTc]Tc-PSMA-I&S for primary tumor detection in early PCa diagnosis.

Despite high diagnostic accuracy, PSMA-targeted imaging is not devoid of false-positive findings. In our study, [⁹⁹ᵐTc]Tc-PSMA-I&S SPECT/CT imaging yielded positive results in 41 cases, with 2 cases being false positives. Previous studies have shown that false-positive PSMA PET/CT findings in prostatic tissue can be attributed to various benign conditions, including hyperplasia, inflammatory processes, and glandular fibrosis secondary to repeated biopsies (37). These documented factors may explain the two false-positive cases observed in our study.

PSMA expression levels in PCa demonstrate significant positive correlations with tumor stage, Gleason score, and pre-treatment tPSA levels, with elevated PSMA expression typically indicating increased malignancy (38, 39). Studies have established that abnormally elevated PSMA expression serves as a predictive indicator for PCa recurrence and metastasis (40). Previous studies using both PET ([⁶⁸Ga]Ga−/[¹⁸F]F-PSMA) and SPECT ([⁹⁹ᵐTc]Tc-HYNIC-PSMA) modalities have demonstrated significant associations between SUVmax and clinical parameters including tPSA and Gleason score (10, 34, 41). Consistent with these findings, our study revealed similar correlations through semi-quantitative analysis of [⁹⁹ᵐTc]Tc-PSMA-I&S SPECT/CT imaging, where SUVmax showed positive associations with tPSA, Gleason score, risk stratification, and disease advancement. Importantly, patients with tPSA ≤20 ng/mL, Gleason score ≤7, low-intermediate risk classification, or non-metastatic disease exhibited significantly lower SUVmax values than their counterparts, underscoring SUVmax’s utility in risk stratification.

Early detection of metastatic disease in PCa patients is crucial for developing effective treatment strategies and avoiding unnecessary major surgical interventions. Multiple studies have demonstrated that PSMA PET/CT exhibits superior efficacy in detecting distant metastases in primary PCa patients compared to conventional imaging methods. This modality accurately reflects the degree of malignancy and disease staging while reducing the need for repeated examinations and invasive biopsies (42–45). Our findings demonstrate that [⁹⁹ᵐTc]Tc-PSMA-I&S SPECT/CT serves as a valuable and reliable tool for detecting advanced disease. In our patient cohort, this imaging modality successfully identified metastatic lesions across multiple sites: lymph node involvement in 56.4% of patients, bone metastases in 48.7%, and visceral metastases in 2.6%. Notably, lymph nodes emerged as the predominant site of extra-prostatic spread.

Direct comparative analysis with Ga-PSMA PET/CT was not conducted in our study, as this imaging modality was not available at our institution during the study period. However, existing literature demonstrates that Tc-PSMA imaging exhibits comparable diagnostic performance to PSMA PET/CT in metastatic evaluation. Albalooshi et al. (18) systematically compared the diagnostic efficacy of Tc-PSMA versus Ga-PSMA PET/CT in 28 patients with prostate cancer (PCa). The investigators reported no statistically significant differences between the two imaging modalities in detecting lymph node and distant disease (p > 0.05). Similarly, Fallahi et al. (46) conducted a comparative study involving 22 PCa patients and demonstrated equivalent detection rates of lymph node and distant metastases with ⁹⁹ᵐTc-PSMA SPECT/CT compared to Ga-PSMA PET/CT imaging. Furthermore, Singh et al. (47) indicated that whole-body Tc-PSMA combined with regional SPECT/CT represents a viable alternative to Ga-PSMA PET for detecting advanced metastatic prostate cancer and evaluating therapeutic response to PSMA-based radioligand therapy. Concurrently, patient selection for Lu-PSMA radioligand therapy (RLT) necessitates sequential PSMA imaging followed by therapeutic monitoring, imposing a substantial economic burden on these patients. Within this clinical context, SPECT/CT imaging, characterized by lower costs and greater accessibility, represents a practical alternative that may improve patient compliance and enhance adherence to standardized monitoring protocols (48, 49).

A distant metastasis risk prediction model based on SUVmax can serve as a factor for evaluating distant metastases. During visual assessment, extra-prostatic distant lesions showed heterogeneity and false-positive rates. When pathological results are unavailable, this may influence treatment selection. Based on our results, an optimal SUVmax value of 14.45 with 92% sensitivity may provide reference for distant metastasis diagnosis. Furthermore, the prediction model based on SUVmax demonstrated an area under the ROC curve of 0.84, effectively distinguishing high-risk PCa patients. Bjurlin et al. (50) proposed that prediction models for high-risk PCa should primarily have high sensitivity to screen for patients with higher malignancy and metastatic risk while maintaining good specificity. Our study shows that the [⁹⁹ᵐTc]Tc-PSMA-I&S SPECT/CT prediction model achieved sensitivity and specificity of 100 and 58%, respectively, (cutoff value 10.85), indicating its predictive value in PCa risk stratification.

However, this study has certain limitations. First, the retrospective, single-center design coupled with a limited sample size (n = 48, including 39 prostate cancer cases) constrains statistical power and generalizability to some extent. Future validation through larger, multicenter prospective studies will be necessary. Second, while the composite reference standard used for metastatic disease validation is clinically appropriate, it introduces uncertainty in specificity assessment since not all lesions underwent histopathological confirmation. Third, the PSMA molecular probe utilized in this study undergoes urinary excretion, which may attenuate metastatic signals near the bladder and kidneys, potentially masking tumor lesions in these regions. Furthermore, our study lacks direct comparison with [68Ga]Ga-PSMA PET/CT, which represents the current imaging gold standard for PSMA-targeted imaging. Future prospective studies incorporating head-to-head comparisons between these imaging modalities will provide valuable insights into their relative diagnostic performance and clinical utility.

In conclusion, our study demonstrates that Tc-PSMA-I&S SPECT/CT imaging constitutes a safe, reliable, and non-invasive diagnostic approach for prostate cancer (PCa), demonstrating efficacy in risk stratification of primary PCa patients and detection of distant metastases. This holds significant value for guiding therapeutic strategies. In economically underdeveloped regions with limited PET/CT availability, it may be considered as an alternative or supplementary method to PSMA PET/CT.