Search Results (85)

Purpose: Prostate-specific membrane antigen (PSMA) is a well-established molecular target in prostate cancer (PCa). Both radionuclide imaging and near-infrared fluorescence (NIRF) imaging offer high sensitivity for in vivo tumor detection. PSMA-targeted dual-modality probes integrating these two imaging techniques provide complementary preoperative and intraoperative tumor visualization, thereby improving surgical guidance in PCa. In this study, we aimed to develop a novel dual-labeled PSMA probe combining radioactive and fluorescent properties to achieve precise tumor delineation during radical prostatectomy (RP). Methods: A high-affinity PSMA-targeted fluorescent probe (PSMA-DF) was synthesized using solid-phase synthesis. Subsequent radiolabeling with the radionuclide [⁶⁸Ga]Ga yielded the successful generation of a dual-modal PSMA-targeted molecular probe, namely [⁶⁸Ga]Ga-PSMA-DF. The probe was systematically evaluated both in vitro and in vivo, and its safety profile was assessed through acute toxicity testing. Tumor-bearing nude mouse models were established using PSMA-positive 22Rv1 and PSMA-negative PC-3 PCa cell lines. Imaging performance, tumor-targeting specificity, and biodistribution of the probe were comprehensively evaluated using micro-PET imaging, in vivo fluorescence imaging, and biodistribution studies. Results: High-quality and high-purity PSMA-DF was successfully prepared, which exhibited excellent optical properties. Following radiolabeling with [⁶⁸Ga]Ga, a dual-modality radionuclide-fluorescence probe ([⁶⁸Ga]Ga-PSMA-DF) was successfully constructed. In vitro cellular uptake studies demonstrated that 22Rv1 cells had relatively high uptake of the probe, reaching 7.34 ± 0.55 IA%/10⁶ cells at 120 min. In contrast, PC-3 cells and blocked 22Rv1 cells displayed minimal uptake, confirming the specific targeting ability of the probe. In vivo evaluations were conducted on tumor-bearing mice using micro-PET/CT and NIRF imaging. The results revealed that [⁶⁸Ga]Ga-PSMA-DF achieved high specific tumor accumulation in 22Rv1 xenografts, with the peak tumor uptake (SUVmax = 1.748 ± 0.132) and tumor-to-muscle ratio (11.542 ± 1.511) observed at 120 min. Notably, high-contrast fluorescence imaging was also achieved at later time points, yielding a tumor-to-background ratio (TBR) of 6.559 ± 1.415 at 48 h. Notably, ex vivo biodistribution data were consistent with in vivo imaging findings. Conclusions: This preclinical study demonstrates that [⁶⁸Ga]Ga-PSMA-DF exhibits high and specific uptake in PCa models, supporting its potential as a dual-modality tracer for both PET/CT imaging and real-time intraoperative fluorescence guidance during PCa surgery. Full article

Background: Radiotherapy (RT) combined with androgen deprivation therapy (ADT) is a standard treatment for non-metastatic high-risk (HR) prostate cancer (PC). However, the benefit of elective nodal irradiation (ENI) in clinically node-negative (cN0) patients, although suggested, remains controversial, particularly in the elderly. We report the outcomes of elderly HR PC patients treated with prostate-only RT (PORT) and ADT in a “real-word” setting. Methods: Between 2016 and 2022, 43 consecutive elderly patients (median age 76 years) with HR- or very HR-PC according to NCCN criteria version 1.2026 (cN0, cT3-cT4 and/or ISUP Grade Group 4–5 and/or PSA serum levels at diagnosis ≥ 20 ng/mL) were treated at our institution. All patients were staged with abdominal MRI or CT and bone scan; nineteen patients (44.2%) also underwent 68Ga-PSMA-11 or 18F-fluorocholine PET/CT. All patients received PORT (predominantly moderate hypofractionation, 67.5–70 Gy in 25–28 fractions) and ADT (median duration 24 months). To ensure consistency, all oncological endpoints—Biochemical Failure-Free Survival (BFFS; Phoenix criteria), Disease-Free Survival (DFS), Metastasis-Free Survival (MFS), Prostate Cancer-Specific Survival (PCSS), and Overall Survival (OS)—were calculated from a unified time-zero (initiation of first oncological treatment). DFS was defined as a composite endpoint including biochemical failure, radiological recurrence, or initiation of salvage therapy. Results: at a median follow-up of 60 months, no patient reached the Phoenix threshold, resulting in a 100% 5- and 7-year BFFS. However, 4 patients (9.3%) experienced radiological recurrence detected via PET/CT before reaching the nadir + 2 threshold, yielding an estimated 5-year and 7-year DFS of 94.7% and 71.8%, respectively. The 5- and 7-year MFS was of 97.6% and 88.7%, respectively. Seven deaths occurred, all non-PC related, resulting in a 5-year OS of 86.7% and a Prostate Cancer-Specific Survival of 100%. Gastrointestinal toxicity was notably low (no acute or late G3-G4 events). Conclusions: Our findings suggest that PORT, when combined with long-term ADT and modern staging, provides excellent disease control and a favorable safety profile in elderly HR PC patients. Given the high rate of competing mortality in this population, treatment de-escalation via PORT appears to be a clinically reasonable strategy. These results are hypothesis-generating and warrant validation in prospective randomized trials. Full article

Castration-resistant prostate cancer presents radiotherapeutic challenges, especially in optimizing the cytosolic internalization of therapeutic radiopharmaceuticals. This research aimed to design and evaluate in vitro, a new dimeric radiopharmaceutical, [¹⁷⁷Lu]Lu–iPSMA–iGRP78, which combines PSMA and GRP78 inhibitors in a heterodimeric radioligand to improve the radionuclide internalization and cytotoxicity efficacy. Molecular docking showed that the dimer iPSMA–iGRP78 presents a higher affinity for GRP78 (CNN-docking score: −14.0 kcal·mol⁻¹, pKi: 10) and for PSMA (CNN-docking score: −17.0 kcal·mol⁻¹, pKi: 11.5) compared to the monomers iGRP78 (CNN-docking score: −11.0 kcal·mol⁻¹, pKi: 9.4) and iPSMA (CNN-docking score: −13.9 kcal·mol⁻¹, pKi: 10.2). The saturation binding assay using LNCaP cells (PSMA+, CS-GRP78+) showed an affinity (K_d) of 1.883 nM for [¹⁷⁷Lu]Lu–iPSMA–iGRP78 and 2.245 nM for [¹⁷⁷Lu]Lu–iPSMA. The dimeric radiopharmaceutical achieved 10.44 ± 2.43% cytosolic internalization and 4.81 ± 0.94% nuclear internalization, while the [¹⁷⁷Lu]Lu–iPSMA monomer showed 6.45 ± 0.60% cytosolic internalization and no uptake in the cell nucleus. In PC3 cells (PSMA–, CS-GRP78–), [¹⁷⁷Lu]Lu–iPSMA–iGRP78 uptake was negligible, demonstrating specificity. Treatment with the dimeric radiopharmaceutical reduced cell viability (69.93 ± 4.85% of dead cells) significantly more than [¹⁷⁷Lu]Lu–iPSMA (38.63 ± 6.13% of dead cells). In conclusion, conjugation of a GRP78 inhibitor to [¹⁷⁷Lu]Lu–iPSMA improves the radionuclide internalization and cytotoxicity in prostate cancer cells, suggesting that the bispecific radiopharmaceutical is a promising strategy in prostate cancer treatment. Full article

Background/Objectives: Radiolabeled biomolecules specifically targeting overexpressed structures on tumor cells hold great potential for prostate cancer (PCa) imaging and therapy. Due to heterogeneous target expression, single radiopharmaceuticals may not detect or treat all lesions, while simultaneously applying two or more radiotracers potentially improves staging, stratification, and therapy of cancer patients. This study explores a dual-tracer SPECT approach using [¹¹¹In]In-RM2 (targeting the gastrin-releasing peptide receptor, GRPR) and [^99mTc]Tc-PSMA-I&S (targeting the prostate-specific membrane antigen, PSMA) as a proof of concept. To mimic heterogeneous tumor lesions in the same individual, we aimed to establish a dual xenograft mouse model for preclinical evaluation. Methods: CHO-K1 cells underwent lentiviral transduction for human GRPR or human PSMA overexpression. Six-to-eight-week-old female immunodeficient mice (NOD SCID) were subsequently inoculated with transduced CHO-K1 cells in both flanks, enabling a dual xenograft with similar target density and growth of both xenografts. Respective dual-isotope imaging and γ-counting protocols were established. Target expression was analyzed ex vivo by Western blotting. Results: In vitro studies showed similar target-specific binding and internalization of [¹¹¹In]In-RM2 and [^99mTc]Tc-PSMA-I&S in transduced CHO-K1 cells compared to reference lines PC-3 and LNCaP. However, in vivo imaging showed negligible tumor uptake in xenografts of the transduced cell lines. Ex vivo analysis indicated a loss of the respective biomarkers in the xenografts. Conclusions: Although the technical feasibility of a dual-tracer SPECT imaging approach using ¹¹¹In and ^99mTc has been demonstrated, the potential of [^99mTc]Tc-PSMA-I&S and [¹¹¹In]In-RM2 in a dual-tracer cocktail to improve PCa diagnosis could not be verified. The animal model, and in particular the transduced cell lines developed exclusively for this project, proved to be unsuitable for this purpose. The in/ex vivo experiments indicated that results from an in vitro model may not necessarily be successfully transferred to an in vivo setting. To assess the potential of this dual-tracer concept to improve PCa diagnosis, optimized in vivo models are needed. Nevertheless, our strategies address key challenges in dual-tracer applications, aiming to optimize future SPECT imaging approaches. Full article

Background: Metastatic prostate cancer (mPrC), with a median survival of under 2 years, represents an important unmet medical need which may benefit from the development of more effective targeted drug delivery systems. Several cell surface receptors have been identified as candidates for targeted drug delivery to mPrC cells; however, these receptors were selected for their overabundance on PrC cells rather than for their suitability for targeted delivery and uptake of cytotoxic drug payloads. Methods: We describe a novel, unbiased strategy to isolate peptides that fulfill functional criteria required for effective intracellular drug delivery and the specific cytotoxicity of PrC cells without prior knowledge of the targeted receptor. Phage clones displaying 7-mer cyclic peptides were negatively selected in vivo and then positively biopanned through a series of parent and drug-resistant mPrC cells. Peptides from the internalized clones were then subjected to a panel of biochemical and functional tests that led to the selection of several peptide candidates. Results: The selected peptides do not bind PSMA. Peptide-drug conjugates (PDCs) incorporating one of the peptides selectively killed wild-type and drug-resistant PrC cell lines and patient PrC cells but not normal prostate tissue cells in vitro. The PDC also halted the growth of PC3 tumors in a xenograft model. Conclusions: Our study demonstrates that adding unbiased, functional criteria into drug carrier selection protocols can lead to the discovery of novel peptides with appropriate properties required for effective targeted drug delivery into target cancer cells. Full article

Prostate cancer is the second leading cause of cancer-related death in men, with metastatic castration-resistant prostate cancer (mCRPC) and bone metastases representing a critical clinical challenge. Although radium-223 (Ra-223) is approved for treating mCRPC with bone metastases, its efficacy remains limited, necessitating the development of more effective therapies. This study investigates the therapeutic potential of ¹⁷⁷Lu-PSMA-617, a PSMA-targeted radiopharmaceutical, in a murine model of prostate cancer bone metastases. To our knowledge, this is the first study to systematically evaluate ¹⁷⁷Lu-PSMA-617 in an orthotopic bone metastatic prostate cancer model, providing a clinically relevant preclinical platform to assess both imaging and therapeutic performance. We conducted comprehensive preclinical evaluations, including synthesis, stability analysis, cell binding assays, nuclear imaging, in vivo biodistribution, pharmacokinetics, and antitumor efficacy. The synthesis of ¹⁷⁷Lu-PSMA-617 demonstrated high radiochemical yield (99.2%), molar activity (25.5 GBq/μmol), and purity (>98%), indicating high product quality. Stability studies confirmed minimal release of free Lutetium-177, maintaining the compound’s integrity under physiological conditions. In vitro assays showed selective binding and internalization in PSMA-positive LNCaP prostate cancer cells, with negligible uptake in PSMA-negative PC-3 cells. In vivo biodistribution studies demonstrated efficient tumor targeting, with peak uptake in LNCaP tumors (23.31 ± 0.94 %IA/g) at 4 h post-injection. The radiopharmaceutical exhibited favorable pharmacokinetics, with high tumor-to-background ratios (tumor-to-blood, 434.4; tumor-to-muscle, 857.4). Therapeutic efficacy was confirmed by significant survival extension in treated mice (30.7% for 37 MBq and 53.8% for 111 MBq), with median survival times of 34 and 40 days, respectively, compared to 26 days in the control group. Radiation dosimetry analysis indicated a favorable safety profile with a calculated effective dose of 0.127 mSv/MBq. These findings highlight the novelty and translational relevance of using ¹⁷⁷Lu-PSMA-617 in a clinically relevant bone metastasis model, reinforcing its potential as a dual-purpose agent for both targeted therapy and molecular imaging in advanced prostate cancer. Full article

In prostate cancer (PCa) surgery, precise tumor margin identification remains challenging despite advances in surgical techniques. This study evaluates the combination of tumor-specific near-infrared imaging with the PSMA-targeting molecule PSMA-914 and optical endomicroscopy (NIR-pCLE) for single-cell-level tumor identification in a preclinical proof of concept. Methods: NIR-pCLE imaging of varying PSMA-914 concentrations was performed on PSMA-positive LNCaP and PSMA-negative PC-3 cells using Cellvizio^® 100 with pCLE Confocal Miniprobes™. To identify optimal PSMA-914 dosing for in vivo imaging, different doses (0–10 nmol) were evaluated using NIR-pCLE, Odyssey CLx imaging, and confocal microscopy in an LNCaP tumor-bearing xenograft model. A proof of concept mimicking a clinical workflow was performed using 5 nmol [⁶⁸Ga]Ga-PSMA-914 in LNCaP and PC-3 tumor xenografts, including PET/MRI, in/ex vivo NIR-pCLE imaging, and microscopic/macroscopic imaging. Results: NIR-pCLE detected PSMA-specific fluorescence at concentrations above 30 nM in vitro. The optimal dose was identified as 5 nmol PSMA-914 for NIR-pCLE imaging with cellular resolution in LNCaP xenografts. PET/MRI confirmed high tumor uptake and a favorable distribution profile of PSMA-914. NIR-pCLE imaging enabled real-time, single-cell-level detection of PSMA-positive tissue, visualizing tumor heterogeneity, confirmed by ex vivo microscopy and imaging. Conclusions: This preclinical proof of concept demonstrates the potential of intraoperative PSMA-specific NIR-pCLE imaging to visualize tissue structures in real time at cellular resolution. Clinical implementation could provide surgeons with valuable additional information, potentially advancing PCa patient care through improved surgical precision. Full article

While multi-parametric magnetic resonance imaging (mpMRI) is known to be a specific and reliable modality for the diagnosis of non-metastatic prostate cancer (PC), positron emission tomography (PET) using ⁶⁸Ga labeled ligands targeting the prostate-specific membrane antigen (PSMA) is known for its reliable detection of prostate cancer, being the most sensitive modality for the assessment of the extra-prostatic extension of the disease and the establishment of a diagnosis, even before biopsy. Background/Objectives: Here, we compared these modalities in regards to the localization of intraprostatic cancer lesions prior to local HDR brachytherapy. Methods: A cohort of 27 patients received both mpMRI and PSMA-PET/CT. Based on 24 intraprostatic segments, two readers each scored the risk of tumor-like alteration in each imaging modality. The detectability was evaluated using receiver operating characteristic (ROC) analysis. The histopathological findings from biopsy were used as the gold standard in each segment. In addition, we applied a patient-based “congruence” concept to quantify the interobserver and intermodality agreement. Results: For the ROC analysis, we included 447 segments (19 patients), with their respective histological references. The two readers of the MRI reached an AUC of 0.770 and 0.781, respectively, with no significant difference (p = 0.75). The PET/CT readers reached an AUC of 0.684 and 0.608, respectively, with a significant difference (p < 0.001). The segment-wise intermodality comparison showed a significant superiority of MRI (AUC = 0.815) compared to PET/CT (AUC = 0.690) (p = 0.006). Via a patient-based analysis, a superiority of MRI in terms of relative agreement with the biopsy result was observed (n = 19 patients). We found congruence scores of 83% (MRI) and 76% (PET/CT, p = 0.034), respectively. Using an adjusted “near total agreement” score (adjacent segments with positive scores of 4 or 5 counted as congruent), we found an increase in the agreement, with a score of 96.5% for MRI and 92.7% for PET/CT, with significant difference (p = 0.024). Conclusions: This study suggests that in a small collective of low-/intermediate risk prostate cancer, mpMRI is superior for the detection of intraprostatic lesions as compared to PSMA-PET/CT. We also found a higher relative agreement between MRI and biopsy as compared to that for PET/CT. However, further studies including a larger number of patients and readers are necessary to draw solid conclusions. Full article

Background: Prostate cancer (PC) is a leading cause of cancer-related deaths in men worldwide. PSMA-directed positron emission tomography (PET) has shown promising results in detecting recurrent PC and metastasis, improving the accuracy of diagnosis and treatment planning. To evaluate an artificial intelligence (AI) model based on [¹⁸F]-prostate specific membrane antigen (PSMA)-1007 PET datasets for the detection of local recurrence in patients with prostate cancer. Methods: We retrospectively analyzed 1404 [¹⁸F]-PSMA-1007 PET/CTs from patients with histologically confirmed prostate cancer. Artificial neural networks were trained to recognize the presence of local recurrence based on the PET data. First, the hyperparameters were optimized for an initial model (model A). Subsequently, the bladder was localized using an already published model and a model (model B) was trained only on a 20 cm cube around the bladder. Finally, two separate models were trained on the same section depending on the prostatectomy status (model C (post-prostatectomy) and model D (non-operated)). Results: Model A achieved an accuracy of 56% on the validation data. By restricting the region to the area around the bladder, Model B achieved a validation accuracy of 71%. When validating the specialized models according to prostatectomy status, model C achieved an accuracy of 77% and model D an accuracy of 77%. All models achieved accuracies of almost 100% on the training data, indicating overfitting. Conclusions: For the presented task, 1404 examinations were insufficient to reach an accuracy of over 90% even when employing data augmentation, including additional metadata and performing automated hyperparameter optimization. The low F1-score and AUC values indicate that none of the presented models produce reliable results. However, we will facilitate future research and the development of better models by openly sharing our source code and all pre-trained models for transfer learning. Full article

Biochemical recurrence (BCR) occurs in 20–50% of patients with localized prostate cancer (PC) after radical prostatectomy (RP). Conventional imaging often fails to detect early local or systemic recurrences at low PSA levels. Positron emission tomography/computed tomography (PET/CT) with 18F-DCFPyL PSMA offers improved sensitivity and specificity for detecting recurrent disease. This study evaluates the diagnostic capability of 18F-DCFPyL PET/CT in early BCR of PC following RP and its impact on therapeutic decision-making and clinical management. Methods: In a prospective study, 85 patients with BCR (PSA 0.2–2.0 ng/mL) and negative conventional imaging underwent 18F-DCFPyL PET/CT. Detection rates (DRs) were analyzed against clinical variables, including PSA levels and PSA doubling time (DT-PSA). Lesions were classified into local recurrence, lymph node involvement, bone, and visceral disease. Therapeutic decisions were adjusted based on PET/CT findings. Results: 18F-DCFPyL PET/CT identified lesions in 53% of patients, with DRs of 31.3%, 60%, and 77.8% for PSA levels <0.5, 0.5–1, and >1 ng/mL, respectively. DRs were significantly associated with shorter DT-PSAs (<6 months: 61.5%). The lesions detected included 22.2% local recurrences, 51.1% lymph node disease, 20% bone, and 6.7% visceral involvement. ROC analysis determined optimal PSA and DT-PSA cutoffs of 0.55 ng/mL and 9.2 months, respectively. Therapeutic strategies were modified in 84.4% of PET-positive cases. Conclusions: 18F-DCFPyL PET/CT demonstrates high sensitivity for detecting recurrent PC at low PSA levels, significantly impacting therapeutic decisions and optimizing clinical management. These findings support its integration into guidelines for managing early BCR of PC. Full article

Focal therapy offers a promising approach for treating localized prostate cancer (PC) with minimal invasiveness and potential cost benefits. High-intensity focused ultrasound (HIFU) and brachytherapy (BT) are among these options but lack long-term efficacy data. Patient follow-ups typically use biopsies and multiparametric MRI (mpMRI), which often miss recurrences. PET/CT with PSMA has emerged as a promising tool for detecting residual disease or recurrence post-treatment, offering higher sensitivity and specificity than traditional imaging. We retrospectively reviewed patients who underwent [⁶⁸Ga]Ga-PSMA-11 PET/CT for biochemical recurrence (BCR) after HIFU or brachytherapy from 2016 to 2024. Out of 22 patients, 32% had HIFU and 68% had brachytherapy. The median time from treatment to PET scan was 77 months, with a median PSA level of 3 ng/mL. [⁶⁸Ga]Ga-PSMA-11 PET/CT identified PC recurrence in 63.6% of cases. Of these, 50% showed prostate recurrence, 14% had lymph node involvement, and 28% had metastatic disease. Focal therapies like HIFU and brachytherapy are effective and minimally invasive options for localized PC. [⁶⁸Ga]Ga-PSMA-11 PET/CT is valuable for detecting recurrence or residual disease, enhancing post-treatment surveillance. Full article

The Prostate cancer (PC) is a major problem all over worldwide and this is the second highest cancer-related mortality rate after lung cancer all over worldwide. At least 299,010 likely cases in men were reported in the US in 2024 and about 35,250 deaths are reported. The overexpression of prostate-specific membrane antigen (PSMA) is a key factor in the progression of prostate cancer and contributes to metastasis in lymph nodes, soft tissues and bones metastasis. The numerous studies have reported that, Glu-ureido-based molecules exhibit high binding affinity for PSMA. The earliest imaging agents developed from this structure were labeled with radioactive halogen isotopes and demonstrated nanomolar binding affinity, leading to exceptional imaging properties. Hence the Glu-ureido chemical moiety is a very important template as inhibitor of PSMA. In this study to explore the chemical structural and electronic features of Glu-Ureido structure with the aid of quantum chemistry computer simulations. In this study, first optimized the structure of this chemical structure using the B3LYP 6311-G (++, d, p) basis set. In this study investigated the maximal quantity of electronic charge transfer (N_max), chemical hardness (η), electrostatic potential, chemical potential (µ) and electrophilicity (ω). By the using Natural Bond Orbital (NBO) analysis, the examination shows that the molecule’s chemically active regions π-electron-electron delocalization within the molecule that contribute to its stability. Full article

Background: New therapeutic strategies for metastatic castration-resistant prostate cancer (mCRPC) have been developed in the past to achieve the best response rates. Most recently, the use of combination therapies has been explored to optimize patient outcomes. Poly(ADP-ribose) polymerase inhibitors (PARPi) may help to treat mCRPC more effectively. Objectives: This study aimed to determine whether the combination of a PARPi with different radiation qualities results in different levels of radiosensitization of PC-3 cells. Methods: The radiosensitizing potential of Olaparib in combination with ¹⁷⁷Lu, ²²³Ra, X-rays and photodynamic therapy (PDT) using the UVA light-activated photosensitizer ortho-iodoHoechst33258 (oIH) was evaluated by determining the clonogenic survival, DNA damage and cell cycle analysis. Results: Here, we show that this combination strategy differentially sensitized PC-3 cells to different radiation qualities. The combination of ¹⁷⁷Lu with Olaparib increased the numbers of persistent double-strand breaks (DSBs) by a factor of 3.3 and cell death in PC-3 cells. Overall, the β-emitter ¹⁷⁷Lu indicated a higher radiosensitization efficacy compared to ²²³Ra, with X-rays corresponding to dose modification factors (DMF) of 1.77, 1.17 and 1.16 respectively. Even in the case of the α-emitter ²²³Ra, the effects were much less pronounced than for ¹⁷⁷Lu. PARPi also showed a slight potentiation of the cytotoxic effects both in co-treatment with X-rays and with PDT. Conclusions: The results of our study indicate a potential role for Olaparib in further optimizing the PSMA radioligand therapy (PRLT) outcomes. However, further evaluation of the combination of PARPi with PRLT is needed to gain more insights into improving the benefit to patients suffering from mCRPC. Full article

Background/Objectives: Prostate cancer (PC) represents the second most diagnosed form of cancer in men on a global scale. Despite the theranostic efficacy of prostate-specific membrane antigen (PSMA) radioligands, there is a spectrum of PC disease in which PSMA expression is low or absent. The gastrin-releasing peptide receptor (GRPR), also known as the bombesin type 2 receptor, has been identified as a target in both the early and advanced stages of PC. The objective of this study was to prepare and preclinically evaluate [^99mTc]Tc-iPSMA-Bombesin ([^99mTc]Tc-iPSMA-BN), estimate dosimetry in healthy subjects, and assess the diagnostic efficacy of the radiotracer in patients with metastatic PC, with the hypothesis of non-inferiority to one of the gold standards, [¹⁸F]-PSMA-1007. Moreover, the potential of [^99mTc]Tc-iPSMA-BN as a theranostic pair with [¹⁷⁷Lu]Lu-iPSMA-BN was investigated. Methods: [^99mTc]Tc-iPSMA-BN was prepared under GMP conditions with radiochemical purities > 95%, showing specific recognition by PSMA and GRP receptors in prostate cancer cells and mice bearing PC tumors. Six healthy volunteers were enrolled, and [^99mTc]Tc-iPSMA-BN SPECT/CT imaging (740 MBq) was performed to estimate the dosimetry. The pilot clinical study included seven mCRPC and four mCSPC patients with prior androgen deprivation therapy. All patients had a recent [¹⁸F]-PSMA-PET/CT scan and were enrolled in this prospective study on their own signed behalf. Volumetric lesion target-to-background ratios (TBRs) were obtained from PET/CT and SPECT/CT images. Results: [^99mTc]Tc-iPSMA-BN effective radiation dose was 1.94 ± 0.39 mSv/740 MBq. A total of 178 lesions were detected via CT, 162 via [¹⁸F]-PSMA-1007 PET, and 155 via [^99mTc]Tc-iPSMA-BN SPECT. Three patients with mCRPC had higher TBR values on SPECT than on PET. [^99mTc]Tc-iPSMA-BN appears to have better lesion detection in patients with aggressive histologic transformation. Two-way ANOVA analysis revealed a significant difference in TBR values between patients with mCRPC and mCSPC (p < 0.05) but no difference between [¹⁸F]-PSMA-1007 and [^99mTc]Tc-iPSMA-BN (p > 0.05). In one patient, [¹⁷⁷Lu]Lu-iPSMA-BN showed a high correlation with [^99mTc]Tc-iPSMA-BN for lesions that concentrated radioactivity. Conclusions: [^99mTc]Tc-iPSMA-BN SPECT/CT is a promising alternative not only for diagnostic purposes but also for broadening the spectrum of PC patients who may benefit from radionuclide theranostics. The results justify the development of a clinical trial involving a significant number of patients with PC. Full article

Background/Objectives: Radioligandtherapy (RLT) with [177Lu]Lu-PSMA has been newly introduced as a routine treatment for metastatic castration-resistant prostate cancer (mCRPC). However, not all patients can tolerate the entire therapeutic sequence, and in some cases, the treatment may prove ineffective. In real-world conditions, the aim is to distinguish between patients who fully benefit from treatment (those who respond effectively and tolerate the entire therapeutic sequence) and those who do not respond or cannot tolerate the entire sequence. This study explores predictive factors to distinguish between fully beneficial RLT treatment patients (FBTP) and not fully beneficial RLT treatment patients (NFBTP). The objective was to enhance the understanding of predictive factors influencing RLT effectiveness and to highlight the significance of machine learning in optimizing patient selection for treatment planning. Methods: Data from 25 mCRPC patients, categorized as FBTP (11) or NFBTP (14) to RLT, were analyzed. The dataset included clinical, imaging, and biological parameters. Data analysis techniques, including exploratory data analysis and feature engineering, were used to develop machine learning models for predicting patient outcomes. Results: Imaging data analysis revealed statistically significant differences in the renal uptake intensity of Choline between the two groups. A discordance of FDG+ and PSMA− was identified as a potential indicator of NFBTP. The integration of biological data enhanced the model’s predictive capability, achieving an accuracy of 0.92, a sensitivity of 0.96, and a precision of 0.96. Adding blood parameters like neutrophils, leukocytes, and alkaline phosphatase greatly increased prediction accuracy. Conclusions: This study emphasizes the significance of an integrated approach that merges imaging and biological data, thereby augmenting the predictive accuracy of patient outcomes in RLT with [177Lu]Lu-PSMA. In particular, including Choline PET among the imaging parameters provides unique insights into the predictive factors affecting RLT efficacy. This approach not only deepens the understanding of predictive factors but also underscores the utility of machine learning in refining the patient selection process for optimized treatment planning. Full article