Molecular Imaging Of Prostate Cancer Research Articles

PD07-08 FIBROBLAST ACTIVATION PROTEIN-SPECIFIC MRI PROVIDES IMPROVED TUMOUR MAPPING IN AN ORTHOTOPIC MODEL OF PROSTATE CANCER COMPARED TO PROSTATE SPECIFIC MEMBRANE ANTIGEN

You have accessJournal of UrologyCME1 May 2022PD07-08 FIBROBLAST ACTIVATION PROTEIN-SPECIFIC MRI PROVIDES IMPROVED TUMOUR MAPPING IN AN ORTHOTOPIC MODEL OF PROSTATE CANCER COMPARED TO PROSTATE SPECIFIC MEMBRANE ANTIGEN Nicole Dmochowska, Valentina Milanova, Anil Shetty, Ramesh Mukkamala, Madduri Srinivasarao, Eric Walser, Phil Low, and Benjamin Thierry Nicole DmochowskaNicole Dmochowska More articles by this author , Valentina MilanovaValentina Milanova More articles by this author , Anil ShettyAnil Shetty More articles by this author , Ramesh MukkamalaRamesh Mukkamala More articles by this author , Madduri SrinivasaraoMadduri Srinivasarao More articles by this author , Eric WalserEric Walser More articles by this author , Phil LowPhil Low More articles by this author , and Benjamin ThierryBenjamin Thierry More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002526.08AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: MRI guided focal therapies of prostate cancer have the potential to reduce treatment related side effects without sacrificing oncological outcomes. Molecular MRI with agents targeted to tumour tissues enhances tumour margin detection and consequently treatment guidance/planning. Prostate specific membrane antigen (PSMA) expression is currently the gold standard for molecular imaging of prostate cancer. Fibroblast activation protein (FAP) is an extracellular transmembrane protein expressed on cells of the tumour microenvironment, particularly in stromal and vascular components. FAP has been gaining momentum as a pan-cancer marker(DOI: 10.2967/jnumed.119.227967) as its overexpression often correlates with cancer severity, including in prostate cancer (DOI: 10.1371/journal.pone.0116683) and has been found to be negligibly expressed in healthy tissue. Our objective was to compare MRI contrast of PSMA-targeting and FAP-targeting magnetic nanoparticles (MNPs) in an orthotopic murine model of prostate cancer. METHODS: Control (no ligand), FAP and PSMA-targeted MNPs were prepared with modification of an MRI agent (FerroTrace, Ferronova) currently undergoing a phase 1 clinical trial. In vitro binding was evaluated in PSMA and FAP positive cell lines. To form orthotopic tumours, LNCaP cells (PSMA+ human prostate cancer) were injected into the prostate. After 4-6 weeks of tumour growth, mice underwent 16.4T T2-weighted 3D MRI 24 hours after intravenous injection of contrast agents. Enhancement of MRI contrast in tumours was quantified by determining the proportion of pixels with low signal intensity throughout regions of interest. Accumulation of MNPs in prostate tumours at 24 hours post injection was confirmed ex vivo by Prussian blue staining. RESULTS: PSMA and FAP-MNPs demonstrated specific binding in vitro. MRI contrast of tumours was increased in FAP (p<0.001) and PSMA-MNPs (p<0.05) but not control MNPs (p>0.05), relative to orthotopic tumours with no injected MNPs. FAP-MNPs provided increased contrast relative to PSMA-MNPs (∼10% enhancement, p<0.05). Increased accumulation of FAP-MNPs in prostate tumours was observed on tissue sections compared to PSMA-MNPs. Control-MNPs showed minimal tumour accumulation. CONCLUSIONS: These results suggest that FAP-targeting MNPs could enhance the MRI of prostate tumours and assist in the delivery of precise focal treatment. Source of Funding: NHMRC Development Grant 1158755 © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e101 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Nicole Dmochowska More articles by this author Valentina Milanova More articles by this author Anil Shetty More articles by this author Ramesh Mukkamala More articles by this author Madduri Srinivasarao More articles by this author Eric Walser More articles by this author Phil Low More articles by this author Benjamin Thierry More articles by this author Expand All Advertisement PDF DownloadLoading ...

The Continuum of Metastatic Prostate Cancer: Interpreting PSMA PET Findings in Recurrent Prostate Cancer.

Simple SummaryMolecular imaging with PSMA PET–CT is more accurate and sensitive than conventional imaging with CT, MRI, and a Technetium-99 bone scan. This new imaging modality will result in more advanced disease being diagnosed earlier which may improve survival, however, it could also lead to overtreatment. Since molecular imaging has the potential to identify disease prior to its detection on conventional imaging, this highlights that advanced prostate cancer exists on a continuum. This review discusses how PSMA PET–CT can be used in managing prostate cancer using clinical scenarios.Conventional imaging has been the standard imaging modality for assessing prostate cancer recurrence and is utilized to determine treatment response to therapy. Molecular imaging with PSMA PET–CT has proven to be more accurate, sensitive, and specific at identifying pelvic or distant metastatic disease, resulting in earlier diagnosis of advanced disease. Since advanced disease may not be seen on conventional imaging, due to its lower sensitivity, but can be identified by molecular imaging, this reveals that metastatic prostate cancer occurs on a continuum from negative PSMA PET–CT and negative conventional imaging to positive PSMA PET–CT and positive conventional imaging. Understanding this continuum, the accuracy of these modalities, and treatment related outcomes based on imaging, will allow the clinician to counsel patients on management. This review will highlight the differences in conventional and molecular imaging in prostate cancer and how PSMA PET–CT can be used for the management of prostate cancer patients in different clinical scenarios, while providing cautionary notes for overtreatment.

Role of molecular imaging in the detection of localized prostate cancer.

Molecular imaging of prostate cancer continues to grow, with recent inclusion of several positron emission tomography (PET) radiotracers into the recent National Comprehensive Cancer Network guidelines and the US Food and Drug Administration approval of prostate-specific membrane antigen (PSMA)-targeted radiotracers. While much of the work for many of these radiotracers is focused on systemic staging and restaging in both newly diagnosed high-risk prostate cancer and biochemically recurrent disease patients, the potential role of molecular imaging for the detection of localized prostate cancer has not yet been fully established. The primary aim of this article will be to present the potential role for molecular imaging in the detection of localized prostate cancer and discuss potential advantages and disadvantages to utilization of both PET/computed tomography (CT) and PET/magnetic resonance imaging (MRI) for this clinical indication of use.

Magnetic polymeric nanobubbles with optimized core size for MRI/ultrasound bimodal molecular imaging of prostate cancer.

Aim: To design MRI/ultrasound (US) dual modality imaging probes with optimized size for prostate cancer imaging by targeting prostate-specific membrane antigen (PSMA). Materials & methods: The PSMA-targeting polypeptide-nanobubbles (PP-NBs) with core size of 400 and 700nm were fabricated and evaluated. Results: With excellent physical property and specificity, PP-NBs of both core size could image PSMA expression in prostate cancer xenografts. Particularly, 400nm PP-NBs generated higher PSMA-specific MRI/US dual modality contrast enhancement than 700nm PP-NBs in correlation with histopathologic findings. Conclusion: Benefit from the smaller core size, 400nm PP-NBs had higher permeability and specificity than 700nm PP-NBs, hence producing better PSMA-specific MRI/US dual modality imaging.

An overview on prostate-specific membrane antigen uptake in malignancies other than prostate cancer: A pictorial essay.

Prostate-specific membrane antigen (PSMA) is a Type II transmembrane glycoprotein which is extremely overexpressed in prostate cancer epithelial cells. Recently, PSMA-targeted small molecule labeled with 68Ga and 99mTc allowed precise molecular imaging of prostate cancer and PSMA-targeted small molecule labeled with 177Lu leads to the development of radionuclide-targeted therapy of prostate cancer. Despite its name, it has been shown that PSMA has been expressed in several malignancies which can be due to significant neovascularization. Present pictorial assay reports the nonspecific tracer uptake in some malignancies during 68Ga-PSMA positron-emission tomography/computed tomography imaging and 99mTc-PSMA scintigraphy.

Heterodimeric Radiotracer Targeting PSMA and GRPR for Imaging of Prostate Cancer-Optimization of the Affinity towards PSMA by Linker Modification in Murine Model.

Prostate-specific membrane antigen (PSMA) and gastrin-releasing peptide receptor (GRPR) are promising targets for molecular imaging of prostate cancer (PCa) lesions. Due to the heterogenic overexpression of PSMA and GRPR in PCa, a heterodimeric radiotracer with the ability to bind to both targets could be beneficial. Recently, our group reported the novel heterodimer BQ7800 consisting of a urea-based PSMA inhibitor, the peptide-based GRPR antagonist RM26 and NOTA chelator. The study reported herein, aimed to improve the affinity of BQ7800 towards PSMA by changing the composition of the two linkers connecting the PSMA- and GRPR-targeting motifs. Three novel heterodimeric analogues were synthesized by incorporation of phenylalanine in the functional linker of the PSMA-binding motif and/or shortening the PEG-linker coupled to RM26. The heterodimers were labeled with indium-111 and evaluated in vitro. In the competitive binding assay, BQ7812, featuring phenylalanine and shorter PEG-linker, demonstrated a nine-fold improved affinity towards PSMA. In the in vivo biodistribution study of [111In]In-BQ7812 in PC3-pip tumor-bearing mice (PSMA and GRPR positive), the activity uptake was two-fold higher in the tumor and three-fold higher in kidneys than for [111In]In-BQ7800. Herein, we showed that the affinity of a bispecific PSMA/GRPR heterodimer towards PSMA could be improved by linker modification.

Real time ultrasound molecular imaging of prostate cancer with PSMA-targeted nanobubbles

Contrast-enhanced ultrasound with microbubbles has shown promise in detection of prostate cancer (PCa), but sensitivity and specificity remain challenging. Targeted nanoscale-contrast agents with improved capability to accumulate in tumors may result in prolonged signal enhancement and improved detection of PCa with ultrasound. Here we report nanobubbles (NB) that specifically targets prostate specific membrane antigen (PSMA) overexpressed in PCa. The PSMA-targeted-NB (PSMA-NB) were utilized to simultaneously image dual-flank PCa (PSMA-positive PC3pip and PSMA-negative PC3flu) to examine whether the biomarker can be successfully detected and imaged in a mouse model. Results demonstrate that active targeting rapidly and selectively enhances tumor accumulation and tumor retention. Importantly, these processes could be visualized and quantified, in real-time, with clinical ultrasound. Such demonstration of the immense yet underutilized potential of ultrasound in the molecular imaging area can open the door to future opportunities for improving sensitivity and specificity of cancer detection using parametric NB-enhanced ultrasound imaging.

Radiolabeled GRPR Antagonists for Imaging of Disseminated Prostate Cancer - Influence of Labeling Chemistry on Targeting Properties.

Radionuclide molecular imaging of Gastrin-Releasing Peptide Receptor (GRPR) expression promises unparalleled opportunities for visualizing subtle prostate tumors, which due to small size, adjacent benign tissue, or a challenging location would otherwise remain undetected by conventional imaging. Achieving high imaging contrast is essential for this purpose and the molecular design of any probe for molecular imaging of prostate cancer should be aimed at obtaining as high tumor-to-organ ratios as possible. This short review summarizes the key imaging modalities currently used in prostate cancer, with a special focus on radionuclide molecular imaging. Emphasis is laid mainly on the issue of radiometals labeling chemistry and its influence on the targeting properties and biodistribution of radiolabeled GRPR antagonists for imaging of disseminated prostate cancer. A comprehensive literature search of the PubMed/MEDLINE, and Scopus library databases was conducted to find relevant articles. The combination of radionuclide, chelator and required labeling chemistry was shown to have a significant influence on the stability, binding affinity and internalization rate, off-target interaction with normal tissues and blood proteins, interaction with enzymes, activity uptake and retention in excretory organs and activity uptake in tumors of radiolabeled bombesin antagonistic analogues. Labeling chemistry has a very strong impact on the biodistribution profile of GRPRtargeting peptide based imaging probes and needs to be considered when designing a targeting probe for high contrast molecular imaging. Taking into account the complexity of in vivo interactions, it is not currently possible to accurately predict the optimal labeling approach. Therefore, a detailed in vivo characterization and optimization is essential for the rational design of imaging agents.

Molecular Imaging of Prostate Cancer Using Radiofluorinated PSMA Ligand

Molecular Imaging of Prostate Cancer Using Radiofluorinated PSMA Ligand

68Ga-RM2 PET in PSMA- positive and -negative prostate cancer patients.

Sixteen men (median age: 74 years, range 50-80 years) with prostate cancer in different stages who had a recent negative (n = 8) or pathologic (n = 8) PSMA PET underwent a subsequent 68Ga-RM2 PET. Both examinations were analyzed qualitatively and quantitatively and compared in terms of pathologic and physiologic tracer distribution. None of the PSMA-negative patients showed any pathological RM2-accumulation. Pathologic PSMA-uptake was observed in 8 patients of whom 5 had pathologic RM2-uptake. The number of patients with a local recurrence was equal in both scans (n = 3). Bone metastases and lymph node metastases were detected in less patients in RM2 PET compared to PSMA PET (n = 4 vs. 7 and n = 2 vs. 5, respectively). In one patient, PSMA-positive liver metastases were not detected in RM2. RM2 PET revealed two additional lesions indicative for bone metastases in two patients with multiple PSMA-positive bone metastases, which had no therapeutic consequence. At least in our small and heterogeneous patient population, 68Ga-RM2 showed no clinically relevant, additional benefit compared to 68Ga-PSMA-11 PET.

Abstract 1145: Biomarker-driven molecular imaging of prostate cancer using the PEG10 promoter

Abstract The retrotransposon-derived paternally expressed gene 10 (PEG10) protein is ordinarily expressed at high levels in the placenta. The over-expression of PEG10 has been documented in a number of malignancies including hepatocellular carcinoma and leukemia. Recently, it was discovered that PEG10 isoforms promoted the progression of prostate adenocarcinoma to a highly lethal non-androgen receptor (AR) driven subtype called aggressive variant prostate cancer (AVPC). In this study, we found that PEG10 was also expressed in castration-resistant PCa possessing constitutively active AR-splice variants in addition to AR-negative AVPC. We subsequently developed a molecular genetic imaging strategy for the non-invasive imaging of PCa by utilizing the cancer specificity of the PEG10 promoter to drive the expression of reporter genes. The transcriptional output of the PEG10 promoter was enhanced to enable high expression of reporter genes by multiple imaging modalities and immunoassay. By using this PEG10 promoter upstream of a reporter gene in a plasmid, we were able to detect PCa by fluorescence and positron emission tomography (PET) imaging after systemic administration of the plasmid in mice. This method also allowed for the detection of PCa by an immunoassay of mouse urine. Our study demonstrates a pre-clinical proof-of-concept that the PEG10 promoter is a powerful and specific tool that can be utilized for non-invasive detection of highly lethal PCa subtypes. This biomarker imaging technology has the potential to improve detection and can be further modified for therapeutic applications. Citation Format: Mariya Shapovalova. Biomarker-driven molecular imaging of prostate cancer using the PEG10 promoter [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1145.

Upcoming role of prostate specific membrane antigen positron emission tomography-computed tomography in detecting occult metastases in prostate cancer

Prostate cancer (PCa) is the second most frequent malignancy in men. Most common sites of disease involvement other than the prostate gland include abdominopelvic lymph nodes and the skeleton. The detection of nodal metastases is of utmost importance to determine prognosis and choice of treatment in patients with PCa. Conventional imaging focuses on morphologic information and takes size criteria for decision-making. Early detection of metastases is further relevant in terms of prognosis and therapy management. Molecular imaging of PCa with Ga-68 prostate-specific membrane antigen (PSMA) positron emission tomography–computed tomography (PET-CT) has recently received significant attention and frequently used with a signature to PCa-specific remark. We presented the case of a 69-year-old male presenting with biochemical recurrence after undergoing surgery and in remission for about a year, where Ga-68 PSMA PET-CT identified additional sites of disease apart from the expected regional bed.

Exploiting the transcriptional specificity of the alpha-methylacyl-CoA racemase AMACR promoter for the molecular imaging of prostate cancer.

The metabolic protein alpha-methylacyl-CoA racemase (AMACR) is significantly overexpressed in prostate cancer compared to the normal prostate and other non-malignant tissue. Though an attractive target, there are no reports in the literature on leveraging the expression of AMACR for the molecular imaging of prostate cancer. Here, we used a molecular-genetic imaging strategy to exploit the transcriptional specificity of the AMACR promoter for the in vivo detection of prostate cancer using the reporter gene luciferase. We performed a stepwise truncation of the promoter and identified a 565 base pair minimal promoter for AMACR that retained both high activity and specificity. Following identification of the minimal promoter for AMACR, we used an advanced two-step transcriptional amplification system to maximize the promoter output. We showed that our optimized AMACR promoter can drive expression of luciferase for molecular imaging in subcutaneous xenograft models of androgen receptor-positive and androgen receptor-negative prostate cancer using a non-replicative adenovirus for gene delivery. Our results provide evidence that the AMACR promoter can be exploited to drive the cancer-specific expression of reporter genes and potentially even be incorporated into conditionally replicative adenoviruses for oncolytic therapy and other applications.

PSMA-Directed Biologically-Guided Radiation Therapy of Castration-Sensitive Oligometastatic Prostate Cancer Patients

Local ablative treatment to oligometastatic (OM) patients can result in long term disease-free survival in cancer patients. The importance of consolidating all tumors in prostate cancer in the modern era is unknown. Stereotactic ablative radiation (SABR) is highly focused, high-dose radiation, but further dose escalation is still limited by target motion, localization uncertainties and difficultly irradiating multiple metastases simultaneously. Biology-guided radiotherapy (BgRT) is currently being developed to utilize PET emission data to guide radiotherapy delivery in real-time and to multiple targets. With this modality, the PET signals act as a biological fiducial that inherently tracks target motion and treatment setup uncertainties. Prostate membrane specific antigen (PSMA) is a cell surface protein that is overexpressed preferentially in prostate cancer and radiolabeled-ligands have been used for unprecedented molecular imaging in prostate cancer. Here we report on a pilot study examining PSMA-directed BgRT using a cohort from our Phase II randomized trial of SABR to men with recurrent low volume (1-3 metastases) metastatic hormone sensitive prostate cancer (HSPC) who have been imaged with PSMA PET-CT. Patients are randomized 2:1 to SABR:observation with minimization to balance assignment by primary intervention, prior hormonal therapy, and PSA doubling time. All men treated with SABR were imaged with PSMA PET-CT at day 1 prior to SABR and day 180 from randomization. Four patients from this trial were used for a proof-of-concept study to compare conventionally planned SABR treatments versus BgRT treatments generated from a prototype treatment planning system (TPS). BgRT treatment plan prescriptions were duplicated from the conventional SABR treatment plans and the dose constraints for organs-at-risk (OARs) followed AAPM TG101 guidelines. No additional dose shaping structures were used for the BgRT plans. All patients had one metastatic site (n= 2 node & n= 2 bone) with an average PTV of 5.1 cc (range = 1.8-9.5 cc). All four BgRT plans met pre-specified planning objectives and were qualitatively acceptable even without the use of optimization structures. The BgRT plans displayed better PTV coverage, V95=96.9±2% versus V95=95.6%±1 for conventional SABR planning, were more heterogeneous [average Dmax of the prescription dose was 149% (range = 137-164%) for BgRT versus 123% (112-131%) for the conventional SABR] and gave more dose on average [Dmean 123% (range = 117-127%) for BgRT versus 112% (range = 109-116%) for conventional SABR] but had similar and in many cases better avoidance of OARs. This is a pilot BgRT planning study from the first randomized Phase II study evaluating the safety and efficacy of SABR in OM HSPC who have been imaged with PSMA PET-CT. Our study suggests comparable treatment plans between conventional and BgRT planned SABR and demonstrates the feasibility of PSMA-directed BgRT-guided SABR for OM HSPC.

Molecular imaging of prostate cancer.

Prostate cancer is a common malignancy with various treatments from surveillance, surgery, radiation and chemotherapy. The institution of appropriate, effective treatment relies in part on accurate imaging. Molecular imaging techniques offer an opportunity for increased timely detection of prostate cancer, its recurrence, as well as metastatic disease. Advancements within the field of molecular imaging have been complex with some agents targeting receptors and others acting as metabolic intermediaries. In this article, we provide an overview of the most clinically relevant radiotracers to date based on a combination of the five states model and the National Comprehensive Cancer Network Guidelines.

Molecular Imaging of Prostate Cancer: Choosing the Right Agent.

See the associated article on page [789][1]. The well-recognized limitations of conventional imaging with CT, MRI, and 99mTc-methylene diphosphonate bone scans have contributed to a revolution in PET imaging of prostate cancer (PCa). A plethora of PET radiotracers has entered preclinical and early

Targeting PSMA by radioligands in non-prostate disease-current status and future perspectives.

Prostate-specific membrane antigen (PSMA) is the up-and-coming target for molecular imaging of prostate cancer. Despite its name, non-prostate-related PSMA expression in physiologic tissue as well as in benign and malignant disease has been reported in various publications. Unlike in prostate cancer, PSMA expression is only rarely observed in non-prostate tumor cells. Instead, expression occurs in endothelial cells of tumor-associated neovasculature, although no endothelial expression is observed under physiologic conditions. The resulting potential for tumor staging in non-prostate malignant tumors has been demonstrated in first patient studies. This review summarizes the first clinical studies and deduces future perspectives in staging, molecular characterization, and PSMA-targeted radionuclide therapy based on histopathologic examinations of PSMA expression. The non-exclusivity of PSMA in prostate cancer opens a window to utilize the spectrum of available radioactive PSMA ligands for imaging and molecular characterization and maybe even therapy of non-prostate disease.

Peptide-Based Radiopharmaceuticals for Molecular Imaging of Prostate Cancer.

Given the high incidence of prostate cancer, there is a continuing need for advances in early detection and in effective treatments. Over the last several years, radiolabeled peptides have been developed, which can target receptors on prostate tumors with high affinity and specificity. These peptides are eliminated from normal tissues rapidly, producing high contrast for PET and SPECT imaging. Receptors of interest for tumor imaging include prostate specific membrane antigen (PSMA), gastrin-releasing peptide receptor (GRPR), and αvβ3 integrin. Because radiolabeled peptides afford high tumor-to-normal tissue uptake ratios, the potential of peptide-based targeted radiotherapy of prostate cancer is being explored. In addition, targeting either of two receptors with one peptide may allow more tumors to be detected and aid in the delineation of early versus advanced disease. Taken together, all these developments in peptide-based imaging and therapy of prostate cancer offer the promise of personalized, molecular medicine for individual patients.

Synthesis and Assessment of Peptide Gd-DOTA Conjugates Targeting Extradomain B Fibronectin for Magnetic Resonance Molecular Imaging of Prostate Cancer.

Contrast enhanced MRI is commonly used in imaging and treatment planning of prostate cancer. However, no tumor targeting contrast agent is commercially available for accurate detection and characterization of prostate cancer with MRI. Extradomain B fibronectin (EDB-FN), an oncoprotein present in aggressive tumors, is a promising molecular target for detection and stratification of high-risk prostate cancer. In this work, we have identified four small peptides (GVK, IGK, SGV, and ZD2) specific to EDB-FN for tumor targeting. In silico simulations of the binding patterns and affinities of peptides to the EDB protein fragment revealed different binding site to different peptide in the ligand-receptor interactions. Tumor specificity and organ distribution of the peptides were assessed using fluorescence imaging in male mice bearing PC-3 human prostate cancer xenografts. Targeted contrast agents were synthesized by conjugating tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) to the peptides in the solid phase, followed by complexation with GdCl3. The contrast agents were characterized by MALDI-TOF mass spectrometry and relaxivity measurements. All four peptide Gd-DOTA conjugates resulted in robust tumor contrast enhancement in MR imaging of the PC3 mouse prostate cancer model. The peptide Gd-DOTA conjugates specific to EDB-FN are promising targeted small molecular macrocyclic contrast agents for MR molecular imaging of prostate cancer.

A PSMA Ligand Labeled with Cobalt-55 for PET Imaging of Prostate Cancer.

Prostate-specific membrane antigen (PSMA) comprises a recognized target for molecular imaging of prostate cancer. As such, radiolabeled PSMA inhibitors are of great value for diagnosis and staging of this disease. Herein, we disclose the preclinical characterization of [55Co]PSMA-617 for positron emission tomography (PET)/x-ray computed tomography (CT) imaging of prostate cancer lesions. By the application of microwave heating, PSMA-617 in acetate buffer (0.4M, pH4.4) was labeled with the radioisotopes cobalt-55/57. The extents of internalization and dissociation constants (K D) were determined against 2-(phosphonomethyl)-pentanedioic acid in two PSMA-positive cell lines, LNCaP, and PC3-PIP, with [57Co]PSMA-617 as a surrogate for [55Co]PSMA-617 (T½ 17.5h, β max 1.5MeV, Iβ 76%). The biodistribution in LNCaP xenograft mice was investigated using [57Co]PSMA-617 and [55Co]PSMA-617 was employed for PET/CT imaging at 1, 4, and 24h and compared to PET/CT scans using [68Ga]PSMA-617. The radiolabeling with cobalt-55/57 was performed in yields greater than 99.5 and 99.8% and radiochemical purities of 99.7 and 98.9%, respectively. The molar-specific activities were 18.2MBq/nmol and 3.3MBq/nmol. The cellular K D were determined to be 4.7nM for LNCaP and 9.8nM for PC3-PIP, correspondingly. Internalization of 76 and 71% of the cell-associated radioactivity was found for LNCaP and PC3-PIP cells after incubation up to 240min, respectively. In regard to the biodistribution in LNCaP xenograft mice, [57Co]PSMA-617 displayed a high and relatively constant uptake in the tumor (12.9%IA/g at 1h to 10.5%IA/g at 24h) with an initial but transient high uptake in the kidneys, adrenals, and spleen. Tumor-to-background ratios improved over time as normal tissue cleared of the radioligand (tumor-to-blood: 26, 258, and 3013; tumor-to-kidney: 0.11, 0.28, and 4.3 at 1, 4, and 24h). PET/CT imaging with [55Co]PSMA-617 in xenograft mice confirmed the high tumor uptake and fast clearance of normal tissues over time and was found superior to imaging with [68Ga]PSMA-617. Radiolabeling of PSMA-617 was achieved in excellent yields and radiochemical purities. Favorable in vitro data comprising low K D values and high extent of internalization was determined for two PSMA-positive cell lines. In xenograft mice, high tumor accumulation and excellent tumor-to-normal tissues ratios were established by biodistribution experiments and PET/CT imaging and, hence, confirm the potential of [55Co]PSMA-617 for delayed clinical imaging of prostate cancer.