Prostate-specific Membrane Antigen Imaging Research Articles

NIMG-14. HEAD-TO-HEAD COMPARISON OF18F-FET PET AND68GA-PSMA-11 PET IN DISTINGUISHING SMALL VOLUME TUMOR PROGRESSION VS TREATMENT-RELATED CHANGE IN POST-STANDARD OF CARE TREATMENT OF HIGH-GRADE GLIOMA USING DYNAMIC ACQUISITION AND KINETIC MODELING

Abstract BACKGROUND The inability to accurately distinguish between tumor progression and treatment-related changes in patients with high-grade glioma on routine imaging can negatively impact patient management and in some cases, outcome. Various imaging methods have been used to address this issue, including 18F-fluoro-ethyl-tyrosine (FET) PET and MR perfusion. However, these methods may not provide reliable results in cases of small lesion size or hemorrhage within the treatment site. The prostate-specific membrane antigen (PSMA) has been observed to be expressed by neovasculature in brain tumors. Since PSMA cannot cross the blood brain barrier, uptake of PSMA in the brain carries high-level of suspicion for residual tumor. Still, further work is needed to better understand PSMA uptake in the tumor bed following standard of care (SOC) treatment and to compare to currently available neuro-oncologic radiotracers, such as FET. We hypothesize that PSMA imaging of glioma neovasculature will provide unique diagnostic information that will aid in the differentiation of small volume tumor progression from treatment-related changes in the post-SOC treatment setting. METHODS Patients who underwent clinical Expanded Access PET/MR imaging with 18F-FET were re-imaged in a research protocol that collected a brain 68Ga-PSMA-11 PET/CT scan, as well as a repeat 18F-FET PET/CT. Kinetic modeling of dynamic radiotracer uptake was performed. Scans were assessed for correlation with subsequent imaging and changes in clinical management. RESULTS All PSMA scans that were performed were concordant with the initial clinical FET scan, subsequent imaging follow up and appropriate changes in clinical management. The PSMA-detected site was confirmed to be tumor in a single case with subsequent tissue sampling. One patient who was started on bevacizumab after their clinical FET demonstrated a significant decrease in uptake on the research FET scan, but persistent uptake on PSMA. CONCLUSION PSMA may effectively show tumor recurrence in post-SOC treatment high-grade glioma patients.

Iodinated PSMA Ligands as XFI Tracers for Targeted Cell Imaging and Characterization of Nanoparticles.

Prostate cancer is the second most commonly diagnosed cancer in men worldwide. Despite this, current diagnostic tools are still not satisfactory, lacking sensitivity for early-stage or single-cell diagnosis. This study describes the development of small-molecule tracers for the well-known tumor marker prostate-specific membrane antigen (PSMA). These tracers contain a urea motif for PSMA-targeting and iodinated aromatic moieties to allow detection via X-ray fluorescence imaging (XFI). Tracers with a triiodobenzoyl moiety allowed the specific targeting and successful imaging of PSMA+ cell lines with XFI. The XFI-measured uptake of 7.88 × 10-18 mol iodine (I) per cell is consistent with the uptake of known PSMA tracers measured by other techniques such as inductively coupled plasma mass spectrometry (ICP-MS). This is the first successful application of XFI to tumor cell targeting with a small-molecule tracer. In addition, iodinated tracers were used for the characterization of quantum dots (QDs) conjugated to PSMA-targeting urea motifs. The resulting targeted QD conjugates were shown to selectively bind PSMA+ cell lines via confocal microscopy. The immobilized iodinated targeting vectors allowed the determination of the tracer/QD ratio via XFI and ICP-MS. This ratio is a key property of targeted particles and difficult to measure by other techniques.

FAP and PSMA Expression by Immunohistochemistry and PET Imaging in Castration-Resistant Prostate Cancer: A Translational Pilot Study.

Prostate-specific membrane antigen (PSMA) is a theranostic target for metastatic prostate cancer (PCa). However, castration-resistant PCa (CRPC) may lose PSMA expression after systemic therapy. Fibroblast activation protein (FAP), expressed by carcinoma-associated fibroblasts in various cancer types, including PCa, has the potential to be an alternative target. In this study, we evaluated FAP expression in CRPC to assess its potential, using PSMA as a comparison. Methods: FAP expression was assessed using immunohistochemistry in 116 CRPC tumors: 78 adenocarcinomas, 11 small cell carcinomas, and 27 anaplastic carcinomas. Correlation analysis between manual scoring and automated scoring was performed on 54 whole-slide sections of metastatic CRPC. Paired FAP and PSMA stains were assessed in tissue microarray cores of CRPC (n = 62), consisting of locally advanced CRPC (n = 9) and metastatic CRPC (n = 53). FAP and PSMA positivity was defined by an immunohistochemistry score of at least 10. To explore the correlation of PSMA and FAP inhibitor (FAPi) PET imaging and immunohistochemistry, a preliminary analysis of 4 patients included in a [68Ga]-FAPi-46 imaging trial (NCT04457232) was conducted. Results: Manual and automated scoring of FAP yielded results with strong correlations. Overall, FAP expression in CRPC was notably lower than PSMA expression (median immunoscores, 14 vs. 72; P < 0.001). Different histologic subtypes of CRPC demonstrated distinct levels of PSMA expression, whereas their FAP expression levels were comparable. Among the 19 PSMA-negative tumors, 11 (58%) exhibited FAP positivity. FAP expression levels in lymph node metastases were significantly lower than those in nonnodal metastases (P = 0.021). Liver metastases showed significant enrichment of tumors with strong FAP expression compared with nonliver lesions (P = 0.016). In the 4 clinical trial patients, the biopsied metastatic lesions showed lower uptake on FAPi PET than on PSMA PET (median SUVmax, 9.6 vs. 14.5), consistent with FAP expression that was lower than PSMA expression in the corresponding tumor biopsy samples (median immunoscores, 30 vs. 160). Conclusion: Because of the low FAP expression levels in CRPC, the utility of FAPi PET imaging may be limited. Although FAPi PET imaging may be further tested in PSMA-negative CRPC, such as small cell carcinoma, other molecular imaging modalities should be evaluated as alternative choices.

Radical Prostatectomy Without Prior Biopsy in Selected Patients Evaluated by 18F-Labeled Prostate-Specific Membrane Antigen-Ligand Positron Emission Tomography/Computed Tomography and Multiparameter Magnetic Resonance Imaging: A Single-Center, Prospective, Single-Arm Trial.

This study aimed to verify the feasibility and short-term prognosis of prostatectomy without biopsy. Patients with a rising PSA level ranging from 4 to 30 ng/mL were scheduled for multiparametric (mp) MRI and 18F-labeled prostate-specific membrane antigen (PSMA) positron emission tomography (PET). Forty-seven patients (cT2N0M0) with Prostate Imaging Reporting and Data System ≥ 4 and molecular imaging PSMA score ≥ 2 were enrolled. All candidates underwent robot-assisted laparoscopic radical prostatectomy without biopsy. Prostate cancer detection rate, index tumors localization correspondence rate, positive surgical margin, complications, postoperative hospital stay, and PSA level in a 6-week postoperative follow-up visit were collected. All the patients with positive mpMRI and PSMA PET were diagnosed with clinically significant prostate cancer. A total of 80 lesions were verified as cancer by pathology, of which 63 cancer lesions were clinically significant prostate cancer. Fifty-one lesions were simultaneously found by mpMRI and PSMA PET. A total of 23 lesions were invisible on either image, and all lesions were ≤ International Society of Urological Pathology 2 or ≤ 15 mm. Forty-five (95.7%) index tumors found by mpMRI combined with PSMA PET were consistent with pathology. Nine patients reported positive surgical margin. Biopsy-free prostatectomy is safe and feasible for patients with evaluation strictly by mpMRI combined with 18F-PSMA PET/CT.

PSMA-Targeted Therapy: Advancements in Detection and Treatment Modalities with Dr. Scott T. Tagawa.

Prostate cancer is one of the most challenging malignancies due to its high incidence and prevalence, as it is the most frequently diagnosed non-skin cancer in men. The timely identification of prostate cancer and its metastasis is paramount for ensuring favorable outcomes for patients. Prostate-specific membrane antigen (PSMA) emerges as a promising biomarker for its detection, due to its specificity. This makes it an ideal target for the early identification of a metastatic phenotype. Situated on the membrane of tumor cells, PSMA facilitates the attachment of PSMA-targeting particles, enabling their detection through positron emission tomography (PET) scans with relative ease. Utilizing these imaging agents in conjunction with PET scans enhances the accuracy of prostate cancer tumor detection compared to PET scans alone. The advancement in prostate cancer imaging has paved the way for innovative treatment modalities. Prostate-specific membrane antigen-targeted radionuclide therapies (PSMA-TRT) exploit PSMA imaging agents to target identified prostate cancer malignancies with precise radiation, thereby reducing or eliminating the tumor mass. PSMA-TRT exhibits significant promise in prostate cancer therapy, evident from the notable declines in prostate-specific antigen (PSA) levels post treatment. However, PSMA-TRT carries both beneficial and adverse effects. While it represents a substantial leap forward in tumor cell imaging, PSMA-based antigens, being larger particles than ligands, offer prolonged imaging capabilities. Yet, the long-term effects of PSMA-TRT remain unknown, with the short-term adverse ones including fatigue, nausea, pain flares, and potential radiation exposure to others.

Role of Ga68 Prostate-Specific Membrane Antigen Positron Emission Tomography-Computed Tomography in Prostate Cancer Imaging

AbstractThe introduction of prostate-specific membrane antigen (PSMA) in clinical practice has revolutionized the evaluation of biochemical recurrence (BCR) of prostate cancer after curative-intent treatment. The high expression of this glycoprotein in prostate cancer cells makes PSMA imaging superior to the current conventional staging methods, namely bone scanning and computed tomography. The high capability of PSMA imaging for identifying very small previously undetected lesions has been widely demonstrated in the literature, leading to a rethinking of patient management by treating physicians. The usual and predictable patterns of spread in prostate cancer are still more prevalent, such as spread to pelvic lymph nodes and bone metastasis, but different patterns of disease spread are becoming more commonly recognized with higher reliability because PSMA imaging allows the detection of more usual and unusual lesions than conventional imaging. The expanding use of PSMA positron emission tomography (PET) has also revealed PSMA ligand uptake in diverse nonprostatic diseases, which raised questions about the specificity of this imaging modality. It is important for the reading physician to recognize and understand the usual disease spread, the most prevalent unusual sites of relapse, and the nonprostatic conditions which are PSMA avid not only to heighten the relevancy of reports but also to improve imaging consultancy in multispecialty oncologic practice. This article aims to brief the role of PSMA PET in the initial staging of multitude of clinical scenarios, BCR, castration-resistant prostate cancer, usual and unusual patterns of recurrence and metastatic spread diagnosed with PSMA PET, normal variants, pitfalls, and nonprostatic disorders showing PSMA expression.

Design, synthesis and evaluation of novel prostate-specific membrane antigen-targeted aryl [18F]fluorosulfate PET tracers

The expression of prostate-specific membrane antigen (PSMA) in prostate cancer is 100–1000 times higher than that in normal tissues, and it has shown great advantages in the diagnosis and treatment of prostate cancer. The combination of PSMA and PET imaging technology based on the principle of metabolic imaging can achieve high sensitivity and high specificity for diagnosis. Due to its suitable half-life (109 min) and good positron abundance (97%), as well as its cyclotron accelerated generation, 18F has the potential to be commercialize, which has attracted much attention. In this article, we synthesized a series of fluorosulfate PET tracers targeting PSMA. All four analogues have shown high affinity to PSMA (IC50 = 1.85–5.15 nM). After the radioisotope exchange labeling, [18F]L9 and [18F]L10 have PSMA specific cellular uptake (0.65 ± 0.04% AD and 1.19 ± 0.03% AD) and effectively accumulated in 22Rv1 xenograft mice model. This study demonstrates that PSMA-1007-based PSMA-targeted aryl [18F]fluorosulfate novel tracers have the potential for PET imaging in tumor tissues.

RECIP 1.0 Predicts Progression-Free Survival After [177Lu]Lu-PSMA Radiopharmaceutical Therapy in Patients with Metastatic Castration-Resistant Prostate Cancer.

Response Evaluation Criteria in Prostate-Specific Membrane Antigen Imaging (RECIP) 1.0 is an evidence-based framework to evaluate therapeutic efficacy in metastatic prostate cancer using prostate-specific membrane antigen (PSMA) PET/CT. This study aimed to evaluate the associations of interim PSMA PET/CT by RECIP 1.0 with short-term outcome after radiopharmaceutical treatment. Methods: This multicenter retrospective study included patients with metastatic castration-resistant prostate cancer who underwent [177Lu]Lu-PSMA radiopharmaceutical therapy at 3 academic centers and received PSMA PET/CT at baseline and at 12 wk. Pairs of PSMA PET/CT images were assessed by 5 readers for visual RECIP 1.0. The primary outcome was the association of RECIP with prostate-specific antigen progression-free survival (PSA-PFS) by Kaplan-Meier analysis. Results: In total, 124 of 287 screened patients met the inclusion criteria, with 0 (0%), 29 (23%), 54 (44%), and 41 (33%) of those 124 patients having complete response, partial response, stable disease, or progressive disease (PD) by visual RECIP 1.0, respectively. Patients with visual RECIP PD had a significantly shorter PSA-PFS than those with RECIP stable disease or with RECIP partial response (2.6 vs. 6.4 vs. 8.4 mo; P < 0.001). The median PSA-PFS among patients with RECIP PD versus those with non-RECIP PD was 2.6 versus 7.2 mo (hazard ratio, 13.0; 95% CI, 7.0-24.1; P < 0.001). Conclusion: PSMA PET/CT by RECIP 1.0 after 2 cycles of [177Lu]Lu-PSMA is prognostic for PSA-PFS. PSMA PET/CT by RECIP 1.0 may be used in earlier stages of prostate cancer to evaluate drug efficacy and to predict progression-free survival.

The Role of PSMA PET Imaging in the Classification of the Risk of Prostate Cancer Patients: A Systematic Review on the Insights to Guide an Active Surveillance Approach.

active surveillance (AS) is a suitable strategy for patients with prostate cancer (PCa). Prostate-specific membrane antigen (PSMA) positron emission tomography (PET) imaging is an established tool used to assess PCa. The aim of this review was to evaluate the role of PSMA imaging to guide correct risk-based classification and the AS approach in PCa patients. The Scopus, Embase, Web of Science, Cochrane Library, and PubMed/MEDLINE databases were screened to find relevant published articles. 1774 articles were revealed with the literature search. A total of 1764 articles were excluded after applying exclusion criteria (data not within the field of interest, preclinical papers, conference proceedings, reviews, or editorials). Ten studies were finally included in the review, revealing that PSMA PET could have the ability to guide risk-based classification of PCa and the choice of AS, and to guide the execution of biopsies for the research of high-grade PCa, therefore precluding AS. this systematic review underlined a possible role of PSMA PET imaging in patients with PCa by correctly re-classifying them on the basis of their risk and guiding AS.

Optimization and scale up of production of the PSMA imaging agent [18F]AlF-P16-093 on a custom automated radiosynthesis platform

BackgroundRecent advancements in positron emission tomograph (PET) using prostate specific membrane antigen (PSMA)-targeted radiopharmaceuticals have changed the standard of care for prostate cancer patients by providing more accurate information during staging of primary and recurrent disease. [68Ga]Ga-P16-093 is a new PSMA-PET radiopharmaceutical that demonstrated superior imaging performance in recent head-to-head studies with [68Ga]Ga-PSMA-11. To improve the availability of this new PSMA PET imaging agent, [18F]AlF-P16-093 was developed. The 18F-analog [18F]AlF-P16-093 has been synthesized manually at low activity levels using [18F]AlF2+ and validated in pre-clinical models. This work reports the optimization of the production of > 15 GBq of [18F]AlF-P16-093 using a custom automated synthesis platform.ResultsThe sensitivity of the radiochemical yield of [18F]AlF-P16-093 to reaction parameters of time, temperature and reagent amounts was investigated using a custom automated system. The automated system is a low-cost, cassette-based system designed for 1-pot syntheses with flow-controlled solid phase extraction (SPE) workup and is based on the Raspberry Pi Zero 2 microcomputer/Python3 ecosystem. The optimized none-decay-corrected yield was 52 ± 4% (N = 3; 17.5 ± 2.2 GBq) with a molar activity of 109 ± 14 GBq/µmole and a radiochemical purity of 98.6 ± 0.6%. Run time was 30 min. A two-step sequence was used: SPE-purified [18F]F− was reacted with 80 nmoles of freeze-dried AlCl3·6H2O at 65 °C for 5 min followed by reaction with 160 nmoles of P16-093 ligand at 40 °C for 4 min in a 1:1 mixture of ethanol:0.5 M pH 4.5 NaOAc buffer. The mixture was purified by SPE (> 97% recovery). The final product formulation (5 mM pH 7 phosphate buffer with saline) exhibited a rate of decline in radiochemical purity of ~ 1.4%/h which was slowed to ~ 0.4%/h when stored at 4 °C.ConclusionThe optimized method using a custom automated system enabled the efficient (> 50% none-decay-corrected yield) production of [18F]AlF-P16-093 with high radiochemical purity (> 95%). The method and automation system are simple and robust, facilitating further clinical studies with [18F]AlF-P16-093.

PSMA-based PET as an imaging biomarker of androgen receptor signaling in high-risk localized and locally advanced prostate cancer (PCa).

341 Background: The purpose of this prospective, nonrandomized, pilot imaging study (NCT02420977) is to evaluate prostate-specific membrane antigen (PSMA), [18F]DCFPyL (DCFPyL), as a PET/CT imaging biomarker of androgen receptor (AR) signaling in newly diagnosed PCa. Methods: 23 men with treatment-naïve, newly diagnosed high-risk prostate cancer were enrolled. Patients underwent DCFPyL PET/CT imaging and MRI/ultrasound fusion-guided prostate biopsy before and after 2-3 months of nADT (LHRH agonist and anti-androgen), followed by definitive IMRT. We measured the total number of lesions, lesion location, maximum standardized tumor uptake value (SUVmax), PSA, and changes in those variables between baseline and follow-up scans. Concordance between biopsy pathology results and PSMA imaging parameters before and after ADT was evaluated. Results: 3 patients were excluded after baseline PET/CT due to high-burden metastases, small cell histology, and declining to proceed further. 20 patients remained for evaluation. At baseline, 19/20 and 8/20 had at least 1 avid intraprostatic and extraprostatic lesion, respectively, with a 50 total lesions (28 prostate, 19 nodal, 3 bone); median intraprostatic and extraprostatic SUVmax were respectively 9.6 (range: 3.3-56.8) and 7.0 (range: 2.3-61.9). Post-nADT scans revealed 32 lesions (19 prostate, 11 nodes, 2 bone); median intraprostatic and extraprostatic SUVmax decreased respectively to 4.1 (range 1.9-27.8) and 3.2 (range: 1.7-8.9). 3/19 (15.8%) of the patients demonstrated complete uptake resolution of the avid intraprostatic foci, 15/19 (78.9%) showed decreased uptake (58.3% median decrease in SUVmax), and 1/19 (5.26%) showed increased SUVmax. Of the 8 patients with extraprostatic lesions, 2/8 (25%) demonstrated complete uptake resolution, 5/8 (62.5%) showed partially decreased uptake (66.67% median decrease in SUVmax), and 1/8 (12.5%) showed increased SUVmax. One of the same patients still had 2 lesions, for a total of 13 intraprostatic target lesions. Regarding concordance between pathologic results and PSMA imaging response pre- and post-nADT, 14/19 (73%) had biopsies fully concordant with PSMA scan (i.e. residual tumor and residual PET avidity), 4/19 (21%) had biopsies mostly concordant with the scan (i.e. complete pathologic response with partial PET response or vice versa), and 1/19 (5%) had a biopsy discordant with the PSMA scan (i.e. no pathology response, but complete response on PSMA). Conclusions: Post-nADT PET detected fewer PSMA-positive lesions with overall decreased or resolved tumor uptake, except for 2 separate patients with increased intra- and extraprostatic uptake. 95% of post-nADT PSMA scans were fully or mostly concordant with post-nADT biopsies, suggesting that PSMA scans may be a clinically useful, prognostic imaging biomarker for disease status evaluation post-nADT. Clinical trial information: NCT02420977 .

Diagnostic value of 18F-PSMA-1007 PET/CT combined with prostate specific antigen derived indicators in gray area prostate cancer.

The incidence of prostate cancer is increasing every year, and precision diagnosis and treatment can help reduce unnecessary prostate punctures for prostate cancer patients in the gray area. This study aims to investigate the diagnostic value of 18F-prostate specific membrane antigen (PSMA) imaging combined with prostate specific antigen (PSA)-derived indicators for gray zone prostate cancer. A total of 107 patients who underwent 18F-PSMA PET/CT imaging for suspicious prostate cancer with tPSA of 4 to 10 μg/L (PSA gray zone) in a hospital were retrospectively included, and were divided into a prostate cancer group and a non-prostate cancer group based on pathological findings. Patients underwent PSA testing, 18F-PSMA, and abdominal ultrasound, and age, tPSA, fPSA, f/tPSA, prostate volume, PSA density (PSAD), maximum standardized uptake value (SUVmax), and molecular imaging prostate specific membrane antigen (miPSMA) score were compared between the 2 groups. Multivariate logistic regression was used to analyze the influencing factors the diagnosis of gray zone prostate cancer. Receiver operating characteristic (ROC) curves were constructed to evaluate the efficacy of PSAD and SUVmax alone and in combination in diagnosing gray zone prostate cancer. The volume of the prostate cancer group [42.00(34.00, 58.00) cm3 vs 49.00(41.27, 60.41) cm3] was smaller than that of the non-prostate cancer group (Z=-2.376, P=0.017), and the PSAD [(0.18±0.06) μg/(L·cm3) vs 0.15±0.05 μg/(L·cm3)] and SUVmax [18.63(8.03, 28.57) vs 9.33(5.90, 13.52)] were higher than those in the non-prostate cancer group (both P<0.05). The percentage of miPSMA score ≥2 in the prostate cancer group was higher than that in the non-prostate cancer group (χ2=40.987, P<0.001). PSAD (OR=22.154, 95% CI 1.430 to 873.751, P=0.042) and SUVmax (OR=1.301, 95% CI 1.034 to 1.678, P=0.009) were independent influential factors for the diagnosis of prostate cancer in the gray zone. The optimal cut-off values of PSAD and SUVmax were 0.22 μg/(L·cm3) and 8.02, respectively, and the AUCs for the diagnosis of prostate cancer in the gray zone alone and in combination were 0.628 (95% CI 0.530 to 0.720, P<0.05) and 0.806 (95% CI 0.718 to 0.876, P<0.05), 0.847 (95% CI 0.765 to 0.910, P<0.05), with sensitivities of 41.03%, 76.92%, and 74.36% and specificities of 79.41%, 89.71%, and 92.65%, respectively. PSAD and SUVmax are increased in patients with gray zone prostate cancer, and the combination of PSAD and SUVmax is of high value in diagnosing gray zone prostate cancer.

The Probability of Metastases Within Different Prostate-specific Antigen Ranges Using Prostate-specific Membrane Antigen Positron Emission Tomography in Patients with Newly Diagnosed Prostate Cancer

Background and objectivesThe association between prostate-specific antigen (PSA) level and probability of metastatic disease on prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) has not yet been established in patients with newly diagnosed prostate cancer (PCa). Our objective was to assess the probability of metastatic disease within different PSA ranges using PSMA PET/CT for initial staging of PCa, and to identify both the anatomical distribution and the predictors of metastases on PSMA PET/CT. MethodsIn total, 2193 patients with newly diagnosed PCa were retrospectively studied. PSMA PET/CT was performed for staging purposes between January 2017 and May 2022. The proportion of patients with PSMA-avid metastases, stratified by PSA level, was studied. A vast majority of patients in whom at least one high-risk prognostic factor was present underwent PSMA PET/CT. A multivariable logistic regression analysis was performed to identify the predictors of metastases on PSMA PET/CT using clinical, biochemical, radiological, and pathological variables. Key findings and limitationsThe median PSA level at PSMA PET/CT was 14.1 ng/ml. Any metastatic disease (miN1-M1a-c) was observed in 34.7% (763/2193) of all patients and distant metastases (miM1a-c) in 25.4% (557/2193) of patients. The presence of any metastatic disease increased with PSA levels, being 15.4% in men with PSA levels <10 ng/ml and 87.5% in men with PSA levels >100 ng/ml. The multivariable logistic regression analysis found significant associations between the presence of any metastatic disease and PSA subgroups, clinical tumor stage ≥T2, grade group >3, and radiological tumor stage ≥T3b. Conclusions and clinical implicationsThis is the first large epidemiological study in patients with PCa demonstrating the association between PSA subgroups and metastatic disease on modern imaging PSMA PET/CT. Data from this study can be used to counsel patients on the probability of metastatic disease at the time of PSA screening and to provide guidance on existing guidelines. Patient summaryThe prostate-specific antigen level could be used to assess the risk of metastases on prostate-specific membrane antigen positron (PSMA) emission tomography/computed tomography (PET/CT). This knowledge is valuable for selecting patients who will benefit most from metastatic screening with PSMA PET/CT.

Association of PSMA PET-derived Parameters and Outcomes of Patients Treated for Oligorecurrent Prostate Cancer.

Background Prostate-specific membrane antigen (PSMA) PET is useful in the early detection of oligorecurrent prostate cancer (PCa), but whether PSMA PET parameters can be used to identify patients who would benefit from metastasis-directed therapy (MDT) with radiation or surgery remains uncertain. Purpose To assess the association of PSMA PET parameters with outcomes of patients with oligorecurrent PCa after MDT. Materials and Methods In this retrospective analysis of a single-center phase II trial that enrolled patients with biochemical recurrence of PCa after maximal local therapy and with no evidence of disease at conventional imaging, patients underwent PSMA PET (between May 2017 and November 2021), and unveiled recurrences were treated with MDT. Maximum standardized uptake value (SUVmax) and mean standardized uptake value (SUVmean) and PSMA tumor volume derived using thresholds of 2.5 (SUVmean2.5) and 41% (SUVmean41%), respectively, were recorded for sites of recurrence on PSMA PET scans, and a molecular imaging PSMA score was assigned. These parameters were also corrected for smooth filter and partial volume effects, and the PSMA score was reassigned. Cox proportional hazards models were used to evaluate the relationship between PSMA PET parameters and outcomes. Results A total of 74 men (mean age, 68.3 years ± 6.6 [SD]) with biochemical recurrence of PCa were included. PSMA PET revealed 145 lesions in the entire cohort, of which 125 (86%) were metastatic lymph nodes. Application of the correction factor changed the PSMA score in 88 of 145 lesions (61%). Mean SUVmax, SUVmean2.5, and SUVmean41% were associated with lower risk of biochemical progression (hazard ratio [HR] range, 0.77-0.95; 95% CI: 0.61, 1.00; P = .03 to P = .04). For corrected parameters, mean SUVmax, mean SUVmean2.5, mean SUVmean41%, mean PSMA score, maximum SUVmean2.5, maximum SUVmean41%, and maximum PSMA score were associated with a lower risk of biochemical progression (HR, 0.61-0.98; 95% CI: 0.39, 1.00; P = .01 to P = .04). Conclusion Measured and corrected PSMA PET parameters were associated with biochemical progression in men with oligorecurrent PCa treated with MDT. Clinical trial registration no. NCT03160794 © RSNA, 2023 See also the editorial by Civelek in this issue.

Current Status of Radiolabeled Monoclonal Antibodies Targeting PSMA for Imaging and Therapy.

Prostate cancer (PCa) is one of the most prevalent cancer diagnoses among men in the United States and in several other developed countries. The prostate specific membrane antigen (PSMA) has been recognized as a promising molecular target in PCa, which has led to the development of specific radionuclide-based tracers for imaging and radiopharmaceuticals for PSMA targeted therapy. These compounds range from small molecule ligands to monoclonal antibodies (mAbs). Monoclonal antibodies play a crucial role in targeting cancer cell-specific antigens with a high degree of specificity while minimizing side effects to normal cells. The same mAb can often be labeled in different ways, such as with radionuclides suitable for imaging with Positron Emission Tomography (β+ positrons), Gamma Camera Scintigraphy (γ photons), or radiotherapy (β- electrons, α-emitters, or Auger electrons). Accordingly, the use of radionuclide-based PSMA-targeting compounds in molecular imaging and therapeutic applications has significantly grown in recent years. In this article, we will highlight the latest developments and prospects of radiolabeled mAbs that target PSMA for the detection and treatment of prostate cancer.

Opportunities for prostate-specific membrane antigen hybrid imaging in prostate cancer

Prostate-specific membrane antigen (PSMA) hybrid imaging is apromising new technique gaining importance in the field of prostate cancer (PCa) diagnosis and treatment planning. By combining PSMA radioligands and computed tomography (CT) or magnetic resonance imaging (MRI), PSMA hybrid imaging opens up new diagnostic opportunities. PSMA-PET/CT (PET: positron-emission tomography) is already well established in high-risk PCa for primary staging and tumor localization when biochemical recurrence occurs. Further potential indications for PSMA-PET/CT include tumor detection in the initial work-up before arebiopsy with improved accuracy, the identification of target structures for precise local treatment in recurrent PCa (salvage radiotherapy or radio-guided surgery) as well as aprediction of response to PSMA radioligand therapy. This narrative review is based on arecent literature search and aims to highlight the opportunities of PSMA imaging in different disease stages of PCa.

A cell-impermeable luminogenic probe for near-infrared imaging of prostate-specific membrane antigen in prostate cancer microenvironments

Prostate-specific membrane antigen (PSMA) imaging probes are a promising tool for the diagnosis and image-guided surgery of prostate cancer (PCa). However, PSMA-specific luminescence probes for PCa detection and heterogeneity studies with high imaging contrast are lacking. Here, we report the first near-infrared (NIR) iridium(III) complex for the wash-free and specific imaging of PSMA in PCa cells and spheroids. The conjugation of a PSMA inhibitor, Lys-urea-Glu, to an iridium(III) complex synergizes the PSMA-specific affinity and biocompatibility of the inhibitor with the desirable photophysical properties of the iridium(III) complex, including NIR emission (670 nm), high photostability and a large Stokes shift. The cellular impermeability of the probe along with its strong binding affinity to PSMA enhances its specificity for PSMA, enabling the washing-free luminescent imaging of membrane PSMA with lower cytotoxicity. The probe was successfully applied for selectively visualizing PSMA-expressing cells and for the imaging of PSMA in a multicellular PCa model with good imaging penetration, indicating its potential use in complicated and heterogeneous tumor microenvironments. Furthermore, the probe showed good imaging performance in the PCa-bearing tumor mice via targeting PSMA in vivo. This work provides a novel strategy for the development of highly sensitive and specific NIR probes for PSMA in biological systems in vitro, which is of great significance for the precise diagnosis of PCa and for elucidating PCa heterogeneity.

Vascular Expression of Prostate-specific Membrane Antigen (PSMA) in MiTF Family Translocation Renal Cell Carcinoma and Related Neoplasms.

Multiple studies have demonstrated prostate-specific membrane antigen (PSMA) expression in the neo-vasculature of non-prostate tumors including clear cell renal cell carcinoma (ccRCC). However, PSMA expression in rare renal tumors including MiTF family translocation renal cell carcinoma has not been previously characterized. We examined PSMA expression by immunohistochemistry in a series of MiTF family translocation renal cell carcinomas as well as in several genetically related tumors including alveolar soft part sarcoma and PEComas with TFE3 rearrangements. PSMA expression was also studied in several cases of ccRCC and papillary RCC. Overall, PSMA immunohistochemistry was performed in 61 samples from 58 patients. Vascular PSMA expression was seen with the highest frequency in ccRCC [88% (14/16)] (38% focal, 50% diffuse). Translocation RCC (tRCC) demonstrated the second highest frequency of PSMA expression [71% (22/28)] (57% focal, 14% diffuse), followed by alveolar soft part sarcoma [50% (4/8)] (38% focal, 12% diffuse). No PSMA expression was seen in PEComas with TFE3 rearrangement (0/3) or papillary RCC (0/6). PSMA expression was only present in tumor-associated neo-vasculature. A patient with oligometastatic tRCC underwent 68 Ga-PSMA-11 PET imaging which detected multiple putative metastatic lesions not detected on conventional computed tomography imaging performed 2 weeks prior, supporting the potential utility of PSMA imaging in tRCC. These findings have potential implications for the utility of PSMA guided diagnostic and therapeutic agents in both common and uncommon renal cell carcinoma subtypes as well as genetically related mesenchymal neoplasms.

Head-to-Head Comparison of [18F]F-choline and Imaging of Prostate-Specific Membrane Antigen, Using [18F]DCFPyL PET/CT, in Patients with Biochemical Recurrence of Prostate Cancer.

To analyse diagnostic and therapeutic impact of molecular imaging TNM (miTNM) stage obtained with [18F]DCFPyL versus [18F]F-choline in head-to-head comparison in biochemical recurrence (BCR) of prostate cancer (PCa). Patients with BCR of PCa after radical treatment with previous [18F]F-choline-PET/CT (negative or oligometastatic disease) were recruited to [18F]DCFPyL-PET/CT. Patients were classified according to: grade group, European Association of Urology classification, PSA, PSA doubling time (PSAdt) and PSA velocity (PSAvel). The overall detection rate (DR) and miTNM stage according to PROMISE criteria were assessed for both radiotracers and also correlated (Kappa). The influence of PSA and kinetics on both PET/CT (DR and miTNM) and predictive value of unfavourable kinetics on miTNM were determined. Cut-off PSA, PSAdt and PSAvel values able to predict PET/CT results were determined. Change in miTNM and treatment derived from [18F]DCFPyL information compared with [18F]F-choline were also evaluated. We studied 138 patients. [18F]DCFPyL showed a higher DR than [18F]F-choline (64.5% versus 33.3%) with a fair agreement. [18F]DCFPyL and [18F]F-choline detected T in 33.3% versus 19.6%, N in 27.5% versus 13.8%, and M in 30.4% versus 8.7%. Both tracers' DR showed significant associations with PSA and PSAvel. Significant association was only found between miTNM and PSA on [18F]F-choline-PET/CT (p = 0.033). For [18F]F-choline and [18F]DCFPyL-PET/CT, a PSAdt cut-off of 4.09 and 5.59 months, respectively, were able to predict M stage. [18F]DCFPyL changed therapeutic management in 40/138 patients. [18F]DCFPyL provides a higher DR and superior miTNM staging than [18F]F-choline in restaging BCR, especially with high PSA and unfavourable PSA kinetics, showing a fair agreement to [18F]F-choline.

N-Alkyl Carbamoylimidazoles as Versatile Synthons for the Synthesis of Urea-Based PSMA Inhibitors.

We describe N-alkyl carbamoylimidazoles as readily available and highly versatile synthons for synthesizing urea-based prostate-specific membrane antigen (PSMA) inhibitors. Urea formation proceeded in high yields (>80%) at room temperature under aqueous conditions. All novel compounds were tested for their PSMA inhibitory potency in a cell-based radiometric binding assay. Compound 17 was identified as a novel high-affinity PSMA inhibitor (IC50 = 0.013 μM) suitable for developing an 18F-labeled radioligand for PET imaging of PSMA in prostate cancer.