Prostate-specific Membrane Antigen Imaging Research Articles

Renal Cell Carcinoma: the Oncologist Asks, Can PSMA PET/CT Answer?

To critically review the potential clinical applications of prostate-specific membrane antigen (PSMA) radioactive ligands in renal cell carcinoma (RCC). Radioactive probes targeting PSMA hold promise in several malignancies in addition to prostate cancer, owing to the expression of PSMA by tumor neovasculature. The majority of clear cell RCCs (ccRCC), the most malignant RCC subtype, express PSMA on tumor-associated neovasculature. The endothelium of less aggressive RCC subtypes is PSMA positive in a lower, but still significant percentage of cases. PSMA might therefore represent an interesting theragnostic target in RCC. The preliminary data available suggest a potential role for PSMA-targeting radiopharmaceuticals in complementing conventional imaging for staging ccRCC patients at risk of nodal involvement and oligometastatic disease. Additional applications of PSMA imaging may be the selection and the response assessment of patients receiving anti-angiogenic treatments. The effectiveness of PSMA-targeting radionuclide therapy should also be investigated.

Hybrid Tracers Based on Cyanine Backbones Targeting Prostate-Specific Membrane Antigen: Tuning Pharmacokinetic Properties and Exploring Dye-Protein Interaction.

Prostate cancer surgery is currently being revolutionized by the use of prostate-specific membrane antigen (PSMA)-targeted radiotracers, for example, 99mTc-labeled PSMA tracer analogs for radioguided surgery. The purpose of this study was to develop a second-generation 99mTc-labeled PSMA-targeted tracer incorporating a fluorescent dye. Methods: Several PSMA-targeted hybrid tracers were synthesized: glutamic acid-urea-lysine (EuK)-Cy5-mas3, EuK-(SO3)Cy5-mas3, EuK-Cy5(SO3)-mas3, EuK-(Ar)Cy5-mas3, and EuK-Cy5(Ar)-mas3; the Cy5 dye acts as a functional backbone between the EuK targeting vector and the 2-mercaptoacetyl-seryl-seryl-seryl (mas3) chelate to study the dye's interaction with PSMA's amphipathic entrance funnel. The compounds were evaluated for their photophysical and chemical properties and PSMA affinity. After radiolabeling with 99mTc, we performed in vivo SPECT imaging, biodistribution, and fluorescence imaging on BALB/c nude mice with orthotopically transplanted PC346C tumors. Results: The dye composition influenced the photophysical properties (brightness range 0.3-1.5 × 104 M-1 × cm-1), plasma protein interactions (range 85.0% ± 2.3%-90.7% ± 1.3% bound to serum, range 76% ± 0%-89% ± 6% stability in serum), PSMA affinity (half-maximal inhibitory concentration [IC50] range 19.2 ± 5.8-175.3 ± 61.1 nM) and in vivo characteristics (tumor-to-prostate and tumor-to-muscle ratios range 0.02 ± 0.00-154.73 ± 28.48 and 0.46 ± 0.28-5,157.50 ± 949.17, respectively; renal, splenic, and salivary retention). Even though all tracer analogs allowed tumor identification with SPECT and fluorescence imaging, 99mTc-EuK-(SO3)Cy5-mas3 had the most promising properties (e.g., half-maximal inhibitory concentration, 19.2 ± 5.8, tumor-to-muscle ratio, 5,157.50 ± 949.17). Conclusion: Our findings demonstrate the intrinsic integration of a fluorophore in the pharmacophore in PSMA-targeted small-molecule tracers. In this design, having 1 sulfonate on the indole moiety adjacent to EuK (99mTc-EuK-(SO3)Cy5-mas3) yielded the most promising tracer candidate for imaging of PSMA.

Preclinical investigations and first-in-human application of 152Tb-PSMA-617 for PET/CT imaging of prostate cancer

BackgroundFor almost a decade, terbium radioisotopes have been explored for their potential theragnostic application in nuclear medicine: 152Tb and 155Tb are the radioisotopes identified for PET or SPECT imaging, while 149Tb and 161Tb have suitable decay characteristics for α- and combined β−/Auger-e−-therapy, respectively. In the present study, the application of 152Tb, in combination with PSMA-617 for imaging of prostate-specific membrane antigen (PSMA)-positive prostate cancer, was demonstrated in a preclinical setting and in a patient with metastatic castration-resistant prostate cancer (mCRPC).Results152Tb was produced at the ISOLDE facility at CERN/Geneva, Switzerland, by spallation, followed by on-line mass separation. The chemical separation was performed at Paul Scherrer Institute using chromatographic methods, as previously reported. 152Tb was employed for labeling PSMA-617, and the radioligand was extensively investigated in vitro to demonstrate similar characteristics to its 177Lu-labeled counterpart. Preclinical PET/CT imaging studies performed with mice enabled visualization of PSMA-positive PC-3 PIP tumors, while uptake in PSMA-negative PC-3 flu tumors were absent. Based on these promising preclinical results, 152Tb was shipped to Zentralklinik Bad Berka, Germany, where it was used for labeling of PSMA-617, enabling PET imaging of a patient with mCRPC. PET/CT scans were performed over a period of 25 h post injection (p.i.) of the radioligand (140 MBq). The images were of diagnostic quality, particularly those acquired at later time points, and enabled the detection of the same metastatic lesions and of local recurrent tumor as previously detected by 68Ga-PSMA-11 PET/CT acquired 45 min p.i.ConclusionsThe results of this study demonstrate the successful preparation and preclinical testing of 152Tb-PSMA-617 and its first application in a patient with mCRPC. This work could pave the way towards clinical application of other Tb radionuclides in the near future, most importantly 161Tb, which has promising decay characteristics for an effective treatment of mCRPC patients.

Peripheral ganglia in healthy rats as target structures for the evaluation of PSMA imaging agents

BackgroundThe recent implementation of PET with prostate specific membrane antigen (PSMA)-specific radiotracers into the clinical practice has resulted in the significant improvement of accuracy in the detection of prostate carcinoma (PCa). PSMA-expression in ganglia has been regarded as an important pitfall in prostate carcinoma-PET diagnostics but has not found any practical use for diagnosis or therapy.MethodsWe explored this phenomenon and demonstrated the applicability of peripheral ganglia in healthy rats as surrogates for small PSMA positive lesions for the preclinical evaluation of diagnostic PCa PET probes. Healthy rats were measured with PET/CT using the tracers [18F]DCFPyL, [Al18F]PSMA-11 and [68Ga]PSMA-11. Sections of ganglia were stained with an anti-PSMA antibody. [18F]DCFPyL uptake in ganglia was compared to that in LNCaP tumor xenografts in mice.ResultsWhereas [18F]DCFPyL and [68Ga]PSMA-11 were stable in vivo and accumulated in peripheral ganglia, [Al18F]PSMA-11 suffered from fast in vivo deflourination resulting in high bone uptake. Ganglionic PSMA expression was confirmed by immunohistochemistry. [18F]DCFPyL uptake and signal-to-noise ratio in the superior cervical ganglion was not significantly different from LNCaP xenografts.ConclusionsOur results demonstrated the non-inferiority of the novel model compared to conventionally used tumor xenografts in immune compromised rodents with regard to reproducibility and stability of the PSMA signal. Furthermore, the model involves less expense and efforts while it is permanently available and avoids tumor-growth associated animal morbidity and distress. To the best of our knowledge, this is the first tumor-free model suitable for the in vivo evaluation of tumor imaging agents.

Association of noninvasive, radiographic measurement of prostate-specific membrane antigen (PSMA) expression with response to PSMA-targeted radionuclide therapy (TRT).

5013 Background: Prostate surface membrane antigen (PSMA) is usually overexpressed in PC and is enriched in castration-resistant tumors. PSMA-TRT is of increasing interest to the field. Many in the field of theranostics have assumed that PSMA uptake on imaging is a pre-requisite for response. We have conducted a number of trials which have incorporated PSMA imaging, but have not selected patients for treatment based upon imaging results and performed an analysis examining the relationship between imaging and response. Methods: Men with mCRPC had either planar radiolabeled J591 imaging (111In-J591 and/or 177Lu-J591) or 68Ga-PSMA11 PET/CT. Visual scores were assigned based upon PSMA uptake in tumors compared to liver uptake and scored on a 0-4 scale. Imaging scores were associated with PSA decline (≥30%, ≥50%) using Cox regression analysis. As several studies were dose-escalation in nature with prior demonstration of dose-response, we controlled for dose administered. Results: 216 men with metastatic CRPC, median PSA 72.45ng/dl, were treated with PSMA-TRT as follows: 177Lu-J591 (n=136), 177Lu-PSMA-617 (n=38), Lu-J591 + Lu-PSMA-617 combination (n=6), 225Ac-J591 (n=7), 90Y-J591 (n=29). 116 (53.7%) pts received low dose and 100 (46.3%) high dose as previously defined in the individual studies. 55 (25.5%) pts had low PSMA expression by imaging (VS 0-1) whereas 161 (74.5%) had high PSMA (VS 2-4). High PSMA expression was associated with more frequent PSA decline (≥30%: 39.2 vs 17.9% p=0.003; ≥50%: 27.5 vs 8.9% p=0.004). When controlling for dose level, this association remained significant for low (≥30%: 25 vs 8.6% p=0.04) and high doses of radionuclide therapy (≥50%: 34.9 vs 9.5% p=0.02). 13 (6%) pts with no PSMA uptake (VS=0) had PSA declines. Conclusions: This is the first study to formally analyze response to PSMA-TRT by PSMA imaging expression in an unselected patient population. The level of PSMA expression measured by imaging is associated with the chance of response. However, a subset of patients without any significant PSMA uptake on imaging did demonstrate response to PSMA-TRT, indicating that imaging cannot exclude all patients that might benefit. Clinical trial information: NCT03545165, NCT03276572, NCT03042468, NCT02552394.

Radiopharmaceuticals targeting PSMA for imaging and/or therapy

Targeting the Prostate Specific Membrane Antigen (PSMA) is becoming increasingly more important for the management of prostate cancer patients at various stages. This review article describes selected radiolabelled PSMA inhibitors with optimized radiopharmaceutical properties for imaging and/or therapy.

Bridging the Imaging Gap: PSMA PET/CT Has a High Impact on Treatment Planning in Prostate Cancer Patients with Biochemical Recurrence-A Narrative Review of the Literature.

68Ga- and 18F-labeled prostate-specific membrane antigen (PSMA) molecules have created new opportunities for the unmet diagnostic needs in prostate cancer. The purpose of this article is to give an overview of studies that have examined the role of PSMA PET in treatment planning for prostate cancer patients with biochemical recurrence (BCR). Methods: Medline, Embase, Web of Science, Google Scholar, and Cochrane Central were searched for relevant articles. After excluding the articles that did not fulfill the required criteria, we included in this review 12 publications that reported the impact of PSMA PET on the treatment plan for prostate cancer patients with BCR. Results: All studies in our review emphasized the impact of PSMA PET images on therapy management in prostate cancer patients with BCR. Overall, the impact of PSMA PET/CT on therapy management varied between 30% and 76% among the 1,346 patients included in the review. Upstaging was reported in 32%-67% of the patients. Patients with low prostate-specific antigen values (<0.5 ng/mL) also demonstrated positive lesions, which could not have been detected by means of conventional imaging techniques. Important modifications to the original treatment plan included avoidance of systemic therapy (17%-40%) and PET-directed local therapy (in ≤60% of the patients). Conclusion: PSMA imaging demonstrated a high clinical impact in patients with BCR, with modifications to the original treatment plan occurring among half the patients. Detecting recurrence in BCR can prevent unnecessary toxicity and lead to individualized therapy.

Imaging of Prostate-Specific Membrane Antigen with Small-Molecule PET Radiotracers: From the Bench to Advanced Clinical Applications

In recent years, small-molecule inhibitors of prostate-specific membrane antigen (PSMA) labeled with radionuclides that allow for positron emission tomography (PET) imaging have been extensively studied in many clinical contexts in men with prostate cancer (PCa). The high sensitivity and specificity of these agents for identifying sites of PCa has quickly led to their widespread adoption as a de facto clinical standard of care throughout much of the world. PSMA-targeted PET radiotracers have been particularly well-studied in preoperatively staging men with high-risk PCa, evaluating biochemical recurrence following definitive therapy, and guiding metastasis-directed therapy in patients suspected of having oligorecurrent/oligometastatic disease. Furthermore, the expression of PSMA on the tumor neovasculature of many nonprostate malignancies has enabled a burgeoning subfield concentrated on delineating the potential utility of PSMA-targeted PET agents for imaging other cancers. In this review, we highlight the preclinical development of key small molecules that are now being clinically utilized for PCa imaging, discuss the roles of PSMA-targeted agents in guiding patient management, and consider the role these compounds may play in imaging nonprostate cancers.

Genomic Risk Predicts Molecular Imaging-detected Metastatic Nodal Disease in Prostate Cancer

BackgroundThe Decipher genomic classifier (GC) is increasingly being used to determine metastasis risk in men with localized prostate cancer (PCa). Whether GCs predict for the presence of occult metastatic disease at presentation or subsequent metastatic progression is unknown. ObjectiveTo determine if GC scores predict extraprostatic 68Ga prostate-specific membrane antigen (68Ga-PSMA-11) positron emission tomography (PET) positivity at presentation. Design, setting, and participantsBetween December 2015 and September 2018, 91 PCa patients with both GC scores and pretreatment 68Ga-PSMA-11 PET scans were identified. Risk stratification was performed using the National Comprehensive Cancer Network (NCCN), Cancer of the Prostate Risk Assessment (CAPRA), and GC scores. Outcome measurements and statistical analysisLogistic regression was used to identify factors correlated with PSMA-positive disease. Results and limitationsThe NCCN criteria identified 23 (25.3%) and 68 patients (74.7%) as intermediate and high risk, while CAPRA scores revealed 28 (30.8%) and 63 (69.2%) as low/intermediate and high risk, respectively. By contrast, only 45 patients (49.4%) had high-risk GC scores. PSMA-avid pelvic nodal involvement was identified in 27 patients (29.7%). Higher GC score was significantly associated with pelvic nodal involvement (odds ratio [OR] 1.38 per 0.1 units; p=0.009) and any PSMA-avid nodal involvement (pelvic or distant; OR 1.40 per 0.1 units; p=0.007). However, higher GC score was not significantly associated with PSMA-avid osseous metastases (OR 1.11 per 0.1 units; p=0.50). Limitations include selection bias for patients able to receive both tests and the sample size. ConclusionsEach 0.1-unit increase in GC score was associated with an approximate 40% increase in the odds of PSMA-avid lymph node involvement. These data suggest that patients with GC high risk might benefit from more nodal imaging and treatment intensification, potentially via pelvic nodal dissection, pelvic nodal irradiation, and/or the addition of chemohormonal agents. Patient summaryPatients with higher genomic classifier scores were found to have more metastatic lymph node involvement on prostate-specific membrane antigen imaging.

Revisiting Prostate Cancer Recurrence with PSMA PET: Atlas of Typical and Atypical Patterns of Spread.

The introduction of prostate-specific membrane antigen (PSMA) in clinical practice has revolutionized evaluation of biochemical recurrence 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 CT. 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 oncologists, urologists, and radiation oncologists. The typical 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 detection of more typical and atypical lesions than conventional imaging. Furthermore, it is important for the reading physician to recognize and understand the typical disease spread and the most prevalent atypical prostate cancer relapses, not only to heighten the relevancy of reports but also to improve imaging consultancy in multispecialty oncologic practice. ©RSNA, 2019.

Modeling and Predicting Tumor Response in Radioligand Therapy.

The aim of this work was to develop a theranostic method that allows prediction of prostate-specific membrane antigen (PSMA)-positive tumor volume after radioligand therapy (RLT) based on a pretherapeutic PET/CT measurement and physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling at the example of RLT using 177Lu-labeled PSMA for imaging and therapy (PSMA I&T). Methods: A recently developed PBPK model for 177Lu-PSMA I&T RLT was extended to account for tumor (exponential) growth and reduction due to irradiation (linear quadratic model). Data from 13 patients with metastatic castration-resistant prostate cancer were retrospectively analyzed. Pharmacokinetic/pharmacodynamic parameters were simultaneously fitted in a Bayesian framework to PET/CT activity concentrations, planar scintigraphy data, and tumor volumes before and after (6 wk) therapy. The method was validated using the leave-one-out Jackknife method. The tumor volume after therapy was predicted on the basis of pretherapy PET/CT imaging and PBPK/PD modeling. Results: The relative deviation of the predicted and measured tumor volume for PSMA-positive tumor cells (6 wk after therapy) was 1% ± 40%, excluding 1 patient (prostate-specific antigen-negative) from the population. The radiosensitivity for the prostate-specific antigen-positive patients was determined to be 0.0172 ± 0.0084 Gy-1Conclusion: To our knowledge, the proposed method is the first attempt to solely use PET/CT and modeling methods to predict the PSMA-positive tumor volume after RLT. Internal validation shows that this is feasible with an acceptable accuracy. Improvement of the method and external validation of the model is ongoing.

Development of a Ga-68 labeled PET tracer with short linker for prostate-specific membrane antigen (PSMA) targeting

Glu-Urea-Lys (GUL) derivatives have been reported as prostate-specific membrane antigen (PSMA) agent. We developed derivatives of GUL conjugated with NOTA or DOTA via a thiourea linker and tested their feasibility as PSMA imaging agents after labeling with 68Ga. NOTA-GUL and DOTA-GUL were synthesized and labeled with 68Ga using generator-eluted 68GaCl3 in 0.1 M HCl in the presence of 1 M NaOAc at pH 5.5. The stabilities of 68Ga-labeled compounds in human serum were tested at 37.5 °C. A competitive binding assay was performed using the PSMA-positive prostate cancer cell line 22Rv1 and [125I]MIP-1072 (PSMA-specific binding agent) as a tracer. Biodistribution and micro-PET studies were performed using 22Rv1-xenograft BALB/c nude mice. The radiolabeling efficiency of NOTA-GUL (>99%) was higher than that of DOTA-GUL (92%). The IC50 of Ga-NOTA-GUL was 18.3 nM. In the biodistribution study, tumor uptake of 68Ga-NOTA-GUL (5.40% ID/g) was higher than that of 68Ga-DOTA-GUL (4.66% ID/g) at 1 h. Tumor/muscle and tumor/blood uptake ratios of 68Ga-NOTA-GUL (31.8 and 135, respectively) were significantly higher than those of 68Ga-DOTA-GUL (16.1 and 31.1, respectively). The tumor/kidney uptake ratio of 68Ga-NOTA-GUL was 3.4-fold higher than that of 68Ga-DOTA-GUL. 68Ga-NOTA-GUL showed specific uptake to PSMA positive tumor xenograft and was blocked by co-injection of the cold ligand. In conclusion, we successfully synthesized 68Ga-NOTA-GUL and 68Ga-DOTA-GUL for prostate cancer imaging. 68Ga-NOTA-GUL showed better radiochemical and biodistribution results. 68Ga-NOTA-GUL may be a promising PSMA targeting radiopharmaceutical.

Detection Threshold and Reproducibility of 68Ga-PSMA11 PET/CT in a Mouse Model of Prostate Cancer.

To improve prostate-specific membrane antigen (PSMA)-targeted theranostic approaches, robust murine models of prostate cancer are needed. However, important characteristics of preclinical PSMA imaging-that is, the reproducibility of the imaging signal and the relationship between quantitative cell surface PSMA expression and lesion detectability with small-animal PET/CT-have not been defined yet. Methods: Murine prostate cancer RM1 sublines (ras myc transformed cells of C57BL/6 prostate origin) expressing varying levels of human PSMA were injected into the shoulder of C57BL/6 mice on day 0. 68Ga-PSMA11 PET/CT was performed on days 7 and 8 and interpreted by 2 masked readers to determine interday and interreader reproducibility. PSMA expression was quantified on days 7 and 8 by flow cytometry of fine-needle aspiration tumor biopsy samples. Cell surface PSMA expression was correlated with PET signal. The threshold for PET positivity was based on the clinical Prostate Cancer Molecular Imaging Standardized Evaluation (PROMISE) criteria. Results: The maximum and average percentages of injected 68Ga-PSMA11 activity per gram of tissue (%IA/g) correlated nearly perfectly as determined by 2 independent readers and on 2 separate days (intraclass correlation coefficient, 1.00/0.89 and 0.95/0.88, respectively). The number of PSMA molecules per cell increased from the RM1-yellow fluorescent protein subline (PSMA-; 2,000/cell) to the RM1-low subline (PSMA+; 17,000/cell), the RM1-medium subline (PSMA++; 22,000/cell), and the RM1-PGLS subline (PSMA-positive, green fluorescent protein-positive, and luciferase-positive; PSMA+++; 45,000/cell). Expression levels correlated with the visual positivity rate on 68Ga-PSMA11 PET and with the PSMA PET %IA/g. The PSMA threshold for PET positivity was approximately 20,000 per cell. Signal correlation was close at lower PSMA levels (RM1-low to RM1-medium; 10-23 %IA/g) but was lost at higher PSMA levels (RM1-medium to RM1-PGLS; 23-27 %IA/g). Conclusion: The in vivo relationship between 68Ga-PSMA11 PET/CT and PSMA expression level in a murine model of prostate cancer was robust for lower cell surface PSMA expression levels (≤22,000/cell). Thus, preclinical 68Ga-PSMA11 PET/CT can be used as an imaging biomarker to test PSMA-targeted interventions in murine models.

Structure–activity relationships of succinimidyl-Cys-C(O)-Glu derivatives with different near-infrared fluorophores as optical imaging probes for prostate-specific membrane antigen

Prostate-specific membrane antigen (PSMA), which is overexpressed in malignant prostate cancer (PCa), is an ideal target for imaging and therapy of PCa. We previously reported a PSMA imaging probe, 800CW-SCE, based on succinimidyl-Cys-C(O)-Glu (SCE) for optical imaging of PCa. In this study, we investigated the structure–activity relationships of novel SCE derivatives with five different near-infrared (NIR) fluorophores (IRDye 680LT, IRDye 750, Indocyanine Green, Cyanine 5.5, and Cyanine 7) as optical imaging probes targeting PSMA. An in vitro binding assay revealed that 800CW-SCE, 680LT-SCE, and 750-SCE exhibited higher binding affinity than 2-PMPA, which is known as a PSMA inhibitor. These three SCE derivatives were internalized into PSMA-positive cells (LNCaP cells) but not into PSMA-negative cells (PC-3 cells). In the in vivo imaging study, 800CW-SCE and 750-SCE were highly accumulated in LNCaP tumors but not in PC-3 tumors, and the ratio of LNCaP/PC-3 accumulation of 800CW-SCE was higher than that of 750-SCE. The present study may provide valuable molecular design information for the future development of new PSMA imaging probes based on the SCE scaffold.

Potential use of prostate specific membrane antigen (PSMA) for detecting the tumor neovasculature of brain tumors by PET imaging with 89Zr-Df-IAB2M anti-PSMA minibody.

Tumor angiogenesis has attracted increasing attention because of its potential as a valuable marker in the differential diagnosis of brain tumors as well as a novel therapeutic target. Prostate-specific membrane antigen (PSMA) is expressed by the neovasculature endothelium of some tumors, with little to no expression by the tumor cells or normal vasculature endothelium. The aim of this study was to investigate the potential of PSMA for the evaluation of the tumor neovasculature of various brain tumors and the possibility of detecting PSMA expression in brain tumors using PET imaging with 89Zr-Df-IAB2M (anti-PSMA minibody). Eighty-three tissue specimens including gliomas, metastatic brain tumors, primary central nervous system lymphomas (PCNSL), or radiation necroses were analyzed by immunohistochemical staining with PSMA antibody. 89Zr-Df-IAB2M PET scans were performed in three patients with recurrent high-grade gliomas or metastatic brain tumor. PSMA was highly expressed in the vascular endothelium of high-grade glioma and metastatic brain tumor, whereas PSMA was poorly expressed in the vascular endothelium of PCNSL and radiation necrosis. PSMA expression in high-grade gliomas and a metastatic brain tumor was clearly visualized by PET imaging with 89Zr-Df-IAB2M. Furthermore, a trend toward a positive correlation between the degree of 89Zr-Df-IAB2M uptake and PSMA expression levels in tumor specimens was observed. PET imaging of PSMA using 89Zr-Df-IAB2M may have potential value in the differential diagnosis of high-grade glioma from PCNSL or radiation necrosis as well as in the prediction of treatment efficacy and assessment of treatment response to bevacizumab therapy for high-grade glioma.

Prostate-specific membrane antigen (PSMA) PET-CT imaging in the investigation and management of biochemical recurrence in prostate cancer.

208 Background: It is estimated that within ten years of primary treatment for prostate cancer up to 40% of patients post radical prostatectomy, and up to 50% of patients post radiotherapy will develop disease recurrence. While monitoring of PSA levels is informative of biochemical recurrence, it may precede radiologically detectable recurrence by months to years, and cannot differentiate local/regional recurrence from systemic disease. This represents a management dilemma for treating physicians. The incorporation of PET probes targeting prostate-specific membrane antigen (PSMA) for prostate cancer shows promise for improving the management of patients with prostate cancer, when used alongside existing imaging techniques, like CT, MRI and bone scans. Methods: Retrospective review of all patients referred from our institution for PSMA imaging was carried out. Baseline clinical features were determined and we analyzed impact of PSMA imaging on management outcomes and survival data. Results: 33 patients referred for 68Ga-PSMA-PET imaging were identified. Median age at diagnosis was 65 years (51 -75). The indication for referral in all patients was biochemical recurrence in the absence of radiological evidence of disease by CT imaging and bone scan. Median PSA at time of referral for PSMA scan was 7.3ug/L (1.4ug/L to 87.7ug/L). 100% of patients (n = 33) were upstaged following PSMA imaging, and 30% (n = 10) had more than one site of metastatic disease identified. Most common sites of metastasis were lymph node and bone. Median number of sites of metastatic disease identified by PSMA imaging was one. These results led to a change in management for 96% patients (n = 32). All patients at the time of this review are alive with a median follow up of 13 months, and median progression-free survival of 11 months. Conclusions: PSMA PET-CT directly led to an alteration in the treatment of the majority of patients in this study. This real world data reflects the growing role of PSMA imaging in influencing clinical decisions for prostate cancer patients with biochemical recurrence. Prospective data from randomized studies are awaited to further validate the role of PSMA PET-CT in this patient cohort.

Prostate-specific Membrane Antigen Imaging in Recurrent Medullary Thyroid Cancer: A New Theranostic Tracer in the Offing?

Prostate-specific membrane antigen (PSMA) expression has been shown in neovasculature of various malignancies. Recurrent medullary thyroid cancer (MTC) is difficult to treat. We present the findings on PSMA-positron emission tomography/computed tomography (PET/CT) of a 68-year-old man with MTC, who presented with a recurrent left paratracheal mass and rising calcitonin. The scan revealed significant uptake on PSMA imaging but not on 68Ga-DOTANOC PET/CT. 177Lu-PRRT is one of the therapeutic options in patients with recurrent MTC, but in this case was not possible due to lack of somatostatin receptor expression. Imaging evidence of PSMA expression alerts us to the potential use of 177Lu-DKFZ-PSMA-617 therapy in such patients.

68Ga PSMA-11 PET with CT urography protocol in the initial staging and biochemical relapse of prostate cancer

Background68Ga-labelled prostate specific membrane antigen (PSMA) ligand PET/CT is a promising modality in primary staging (PS) and biochemical relapse (BCR) of prostate cancer (PC). However, pelvic nodes or local recurrences can be difficult to differentiate from radioactive urine. CT urography (CT-U) is an established method, which allows assessment of urological malignancies. The study presents a novel protocol of 68Ga-PSMA-11 PET/CT-U in PS and BCR of PC.MethodsA retrospective review of PSMA PET/CT-U preformed on 57 consecutive patients with prostate cancer. Fifty mL of IV contrast was administered 10 min (range 8–15) before the CT component of a combined PET/CT study, acquired approximately 60 min (range 40–85) after administration of 166 MBq (range 91–246) of 68Ga-PSMA-11. PET and PET/CT-U were reviewed by two nuclear medicine physicians and CT-U by a radiologist. First, PET images were reviewed independently followed by PET/CT-U images. Foci of activity which could not unequivocally be assessed as disease or urinary activity were recorded. PET/CT-U was considered of potential benefit in final interpretation when the equivocal focal activity in PET images corresponded to opacified ureter, bladder, prostate bed, seminal vesicles, or urethra. Student’s T test and Pearson’s correlation coefficient was used for assessment of variables including lymph node size and standardized uptake value.ResultsOverall 50 PSMA PET/CT-U studies were performed for BCR and 7 for PS. Median PSA with BCR and PS were 2.0 ± 11.4 ng/ml (0.06–57.3 ng/ml) and 18 ± 35.3 ng/ml (6.8–100 ng/ml), respectively. The median Gleason-score for both groups was 7 (range 6–10). In BCR group, PSMA PET was reported positive in 36 (72%) patients, CT-U in 11(22%) patients and PET/CT-U in 33 (66%) patients. In PS group, PSMA PET detected the primary site in all seven patients, of which one patient with metastatic nodal disease had negative CT finding. Of 40 equivocal foci (27/57 patients) on PET, 11 foci (10/57 patients, 17.5%) were localized to enhanced urine on PET/CT-U, hence considered of potential benefit in interpretation. Of those, 3 foci (3 patients) were solitary sites of activity on PSMA imaging including two local and one nodal site and 4 foci (3 patients) were in different nodal fields.ConclusionsPET/CT-U protocol is a practical approach and may assist in interpretation of 68Ga-PSMA-11 imaging by delineation of the contrast opacified genitourinary system and matching focal PSMA activity with urinary contrast.

Seduction by Sensitivity: Reality, Illusion, or Delusion? The Challenge of Assessing Outcomes after PSMA Imaging Selection of Patients for Treatment.

> See the associated article on page [1972][1]. Prostate-specific membrane antigen (PSMA) has long been recognized to be an attractive target for evaluating prostate cancer ([1][2]). Over the past 2 decades, several groups have worked to develop imaging agents capable of leveraging the high

Validation of a [Al18F]PSMA-11 preparation for clinical applications

Imaging prostate-specific membrane antigen (PSMA) using positron emission tomography (PET) has been presented so far as the most sensitive and specific with regard to prostate cancer detection, in particular in high-risk prostate cancer patients. Currently, it mainly features Gallium-68 (68Ga) labeled PSMA ligands, notably [68Ga]Glu-urea-Lys(Ahx)-HBED-CC ([68Ga]-PSMA-11) and [68Ga]DOTAGA-FFK (Sub-KuE termed ([68Ga]PSMA-I&T). However, 68Ga has several shortcomings as radionuclide including a short half-life and non-ideal energies. This has motivated consideration of 18F-labeled analogues for PET imaging of prostate cancer.Here, we describe a simple synthesis and validation of a fluorine-18 labeled Glu-urea-Lys(Ahx)-HBED-CC ([Al18F]PSMA-11) for nuclear medicine applications. An efficient method for preparation of [Al18F]PSMA-11 was developed and validated (according to Pharm Eur) for routinely clinical applications. [Al18F]PSMA-11 was reproducibly obtained in radiochemical yields of 84 ± 6% (n = 15) and > 98% radiochemical purity using an improved one-step radiofluorination in aqueous solution. The total (production/preparation) time, including purification, pharmacological formulation of the isolated product and the quality control of the injectable solution was less than 60min. The [Al18F]PSMA-11 was stable over 4h in 1% EtOH/saline selected as injection solution. The solution was sterile, non-pyrogenic and ready for clinical applications after sterile filtration through a 0.22µm membrane filter under sterile conditions. In addition, [Al18F]PSMA-11 exhibited higher uptake and retention in PMSA-expressing LNCap prostate cells as compared to its clinically established 68Ga-labeled analogues [68Ga]PSMA-11 and [68Ga]PSMA-I&T as well as to [68Ga]NOTA-Bn-PSMA. The simple and fast preparation of [Al18F]PSMA-11 combined with its favorable pharmacological properties warrant its translation to a clinical setting. ConclusionThe facile and high-yielding radiosynthesis of [Al18F]PSMA-11as well as its promising in vitro and in-vivo characteristics makes it worthy of clinical development for PET imaging of prostate cancer.