Imaging Agents For Prostate Cancer Research Articles

Synthesis and fluorine-18 radiolabeling of a phospholipid as a PET imaging agent for prostate cancer

IntroductionAltered lipid metabolism and subsequent changes in cellular lipid composition have been observed in prostate cancer cells, are associated with poor clinical outcome, and are promising targets for metabolic therapies. This study reports for the first time on the synthesis of a phospholipid radiotracer based on the phospholipid 1,2-didocosahexaenoyl-sn-glycero-3-phosphocholine (PC44:12) to allow tracking of polyunsaturated lipid tumor uptake via PET imaging. This tracer may aid in the development of strategies to modulate response to therapies targeting lipid metabolism in prostate cancer. MethodsLipidomics analysis of prostate tumor explants and LNCaP tumor cells were used to identify PC44:12 as a potential phospholipid candidate for radiotracer development. Synthesis of phosphocholine precursor and non-radioactive standard were optimised using click chemistry. The biodistribution of a fluorine-18 labeled analogue, N-{[4-(2-[18F]fluoroethyl)-2,3,4-triazol-1-yl]methyl}-1,2-didocosahexaenoyl-sn-glycero-3-phosphocholine ([18F]2) was determined in LNCaP prostate tumor-bearing NOD SCID gamma mice by ex vivo biodistribution and PET imaging studies and compared to biodistribution of [18F]fluoromethylcholine. Results[18F]2 was produced with a decay-corrected yield of 17.8 ± 3.7% and an average radiochemical purity of 97.00 ± 0.89% (n = 6). Molar activity was 85.1 ± 3.45 GBq/μmol (2300 ± 93 mCi/μmol) and the total synthesis time was 2 h. Ex vivo biodistribution data demonstrated high liver uptake (41.1 ± 9.2%ID/g) and high splenic uptake (10.9 ± 9.1%ID/g) 50 min post-injection. Ex vivo biodistribution showed low absolute tumor uptake of [18F]2 (0.8 ± 0.3%ID/g). However, dynamic PET imaging demonstrated an increase over time of the relative tumor-to-muscle ratio with a peak of 2.8 ± 0.5 reached 1 h post-injection. In contrast, dynamic PET of [18F]fluoromethylcholine demonstrated no increase in tumor-to-muscle ratios due to an increase in both tumor and muscle over time. Absolute uptake of [18F]fluoromethylcholine was higher and peaked at 60 min post injection (2.25 ± 0.29%ID/g) compared to [18F]2 (1.44 ± 0.06%ID/g) during the 1 h dynamic scan period. Conclusions and advances in knowledgeThis study demonstrates the ability to radiolabel phospholipids and indicates the potential to monitor the in vivo distribution of phospholipids using fluorine-18 based PET.

The prostate-specific membrane antigen (PSMA)-targeted radiotracer 18F-DCFPyL detects tumor neovasculature in metastatic, advanced, radioiodine-refractory, differentiated thyroid cancer.

Prostate-specific membrane antigen (PSMA; also termed glutamate carboxypeptidase II (GCP II)) is abundantly expressed in prostate cancer. It has been shown recently that PSMA is expressed in neovasculature of differentiated thyroid cancer. In this study, we show that 18F-DCFPyl might detect neovasculature in advanced, metastatic differentiated thyroid cancer (DTC). We first stained the preserved lymph node samples of three patients with DTC who had undergone total thyroidectomy and neck dissection for cervical lymph node metastatic disease to identify PSMA expression, with the PSMA antibody (DAKO Monoclonal). Then, we performed 18F-DCFPyl imaging in two other advanced DTC patients with elevated serum thyroglobulin (Tg), indicative of residual disease. We compared the findings with contemporaneous FDG PET/CT scan, conventional Imaging (CT,MRI) and whole-body scan performed with I123/I131. All the three lymph node samples stained positive for PSMA expression in the neovasculature. In the first imaged patient, 18F-DCFPyl detected activity within the retropharyngeal CT contrast-enhancing lymph node. Compared to FDG PET/CT, the 18F-DCFPyl scan showed a greater SUV (3.1 vs 1.8). In the second imaged patient, 18F-DCFPyl showed intense uptake in the L3 vertebra (not seen on the post treatment 131I scan or the 18F-FDG PET/CT). MRI of the lumbar spine confirmed the presence of sclerotic-lytic lesion at the location, consistent with metastatic disease. Our exploratory study is proof of principle, that the prostate cancer imaging agent 18F-DCFPyl may prove useful for the localization of metastases, in patients with metastatic RAI-refractory DTC by detecting neoangiogenesis within the tumor.

Novel PET imaging methods for prostate cancer.

Prostate cancer is a common neoplasm but conventional imaging methods such as CT and bone scan are often insensitive. A new class of PET agents have emerged to diagnose and manage prostate cancer. The relevant literature on PET imaging agents for prostate cancer was reviewed. This review shows a broad range of PET imaging agents, the most successful of which is prostate specific membrane antigen (PSMA) PET. Other agents either lack the sensitivity or specificity of PSMA PET. Among the available PET agents for prostate cancer, PSMA PET has emerged as the leader. It is likely to have great impact on the diagnosis, staging and management of prostate cancer patients.

A deep learning algorithm to predict coexisting metastatic disease using intraprostatic [F18]DCFPYL PSMA image alone in veterans with prostate cancer.

25 Background: [F18]DCFPyL (PyL) is a PSMA targeted imaging agent for prostate cancer. Independent of manual feature selection, a deep learning algorithm might offer additional insight into the disease biology. We explored the performance of a deep learning algorithm on PyL images of the primary tumor to predict co-existing distant metastases. Methods: 74 veterans with high risk primary prostate cancer tumors were imaged with both PyL PSMA PET/CT and conventional imaging (bone scan and CT or MRI of the abdomen/pelvis). 26% were confirmed with metastatic disease (M1) by conventional imaging. The PyL images of the primary tumor were analyzed with EXINI’s PyL-AI algorithm. Location of the prostate was defined on low dose CT via automatic segmentation using a deep convolutional network. The segmentations were used to map the PyL PET image of the prostate. The image based PyL-AI model was made up of a Conv3D layer of 4 kernels, a Conv3D layer of 8 kernels, a dense layer of 64 nodes followed by a final dense layer with 2 nodes. The model training was performed on the images using 5-fold cross validation with non-overlapping validation sets. The test predictions were compared with ground truth (M1); the area under ROC curve (AUC) was computed to determine the performance of the model in predicting the presence of distant metastases. A logistical regression model from baseline clinicopathologic features of the primary tumor (baseline PSA, biopsy gleason score, percent cores positive, T stage) was created as a comparator. Results: The logistical regression model using clinicopathologic features had an AUC of 0.71, while the PyL-AI model based on intra-prostatic PyL Images alone had an AUC of 0.81 for prediction of metastatic disease as defined by conventional imaging. Adding clinical parameters in the image based PyL-AI model incrementally increased the AUC to 0.82. Conclusions: The image based PyL-AI deep learning model demonstrates a higher predictive accuracy over the logistic model using classical clinicopathologic features. The study is hypothesis generating observation that needs prospective validation in an independent data set.

Research progress of 68Ga-PSMA PET/CT in the diagnosis of prostate cancer

The incidence of prostate cancer has shown an obvious upward trend in recent years. 18F-fluorodeoxyglucose (FDG) is a broad-spectrum imaging agent for cancer, but there is a blind zone in the application of prostate cancer. Therefore, exploring prostate imaging agents with better performance can help to make up the deficiency. At present, there are a number of positron imaging agents for prostate cancer, but the overall advantage is not obvious. Recently, a new imaging agent, 68Ga-prostate specific membrane antigen (PSMA), has been demonstrated its better value in clinical application of prostate cancer. This review summarizes the research progress of 68Ga-PSMA. Key words: Prostatic neoplasms; Prostate-specific membrane antigen; Isotope labeling; Gallium radioisotopes; Positron-emission tomography; Tomography, X-ray computed; Trends

Single vial cold kits optimized for preparation of gastrin releasing peptide receptor (GRPR)-radioantagonist 68Ga-RM2 using three different 68Ge/68Ga generators

68Ga-RM2 is a gastrin releasing peptide receptor (GRPR) antagonist PET (positron emission tomography) radiotracer which is being investigated in clinical trials as a potential prostate cancer imaging agent. Simple, one-step kit formulation of 68Ga-RM2 would facilitate multicentre trials and allow easier integration in hospital radiopharmacy. Herein we report development of three sets of single-vial RM2 cold kits validated for formulation with three respective 68Ge/68Ga generators eluted in 0.6 M, 0.1 M and 0.05 M HCl (hydrochloric acid). Cold kits of varied pH (2, 3, 4 and 5) were prepared using 2 M sodium acetate for three different 68Ge/68Ga generators to determine influence of pH on the radiochemical yield of 68Ga-RM2. Buffer content was optimized with respect to volume of 68GaCl3 eluate to be added (1 mL/2 mL/ 5 mL). Sterility, apyrogenicity and long term stability of cold kits; in vitro and serum stability of 68Ga-RM2 were investigated. In vitro cellular uptake and inhibition studies were performed to demonstrate the specificity of kit-formulated 68Ga-RM2. The radiochemical yield of 68Ga-RM2 formulated from three different generators was observed to be maximum at pH 3 (99 ± 0.5%). Cold kits stored for 6 months at 0 °C also resulted in high radiochemical yield. 68Ga-RM2 exhibited excellent in vitro stability (1 h) and serum stability (1 h). In vitro cellular uptake of 5 ± 0.8% in PC3 cells with >85% inhibition was observed for the 68Ga-RM2 radiotracer indicating its specificity towards GRPR expression. These simple, robust kits shall allow hospitals with different generators to participate in clinical studies of 68Ga-RM2 for screening of GRPR-expressing prostate tumors.

Imaging prostate cancer (PCa) with [99m Tc(CO)3 ]finasteride dithiocarbamate.

This investigation aimed to modify finasteride (1) to finasteride dithiocarbamate (2) for subsequent synthesis of the rhenium analogue (3) and [99m Tc]tricarbonyl complexes (4), to assess its prostate cancer (PCa) targeting potential in a rat model. To validate the identity of (4), reference (3) has been synthesized by using fac-[Net4 ]2 [ReBr3 (CO)3 ] precursor and characterized by 1 H-NMR, 13 C-NMR, ESI-MS, and elemental analysis. The analogue (4) was synthesized by using fac-[99m Tc(H2 O)3 (CO)3 ]+ precursor, and its structure was confirmed by comparative HPLC by using (3) as a reference. Further, the suitability of (4) as a PCa imaging agent was investigated in vitro and in vivo. At room temperature, (4) had ≥99% radiochemical purity and remained ≥84% stable in serum. In preclinical studies, biodistribution of (4) in histopathologically established rat model showed adequately high in vivo uptake in the prostate attracting the possibility of using it for noninvasive imaging of PCa.

Structure-Activity Relationship of (18)F-Labeled Phosphoramidate Peptidomimetic Prostate-Specific Membrane Antigen (PSMA)-Targeted Inhibitor Analogues for PET Imaging of Prostate Cancer.

A series of phosphoramidate-based prostate specific membrane antigen (PSMA) inhibitors of increasing lipophilicity were synthesized (4, 5, and 6), and their fluorine-18 analogs were evaluated for use as positron emission tomography (PET) imaging agents for prostate cancer. To gain insight into their modes of binding, they were also cocrystallized with the extracellular domain of PSMA. All analogs exhibited irreversible binding to PSMA with IC50 values ranging from 0.4 to 1.3 nM. In vitro assays showed binding and rapid internalization (80-95%, 2 h) of the radiolabeled ligands in PSMA(+) cells. In vivo distribution demonstrated significant uptake in CWR22Rv1 (PSMA(+)) tumor, with tumor to blood ratios of 25.6:1, 63.6:1, and 69.6:1 for [(18)F]4, [(18)F]5, and [(18)F]6, respectively, at 2 h postinjection. Installation of aminohexanoic acid (AH) linkers in the phosphoramidate scaffold improved their PSMA binding and inhibition and was critical for achieving suitable in vivo imaging properties, positioning [(18)F]5 and [(18)F]6 as favorable candidates for future prostate cancer imaging clinical trials.

Corrigendum] Synthesis and positron emission tomography evaluation of 18F-Glu-Urea-Lys, a prostate-specific membrane antigen-based imaging agent for prostate cancer

Corrigendum] Synthesis and positron emission tomography evaluation of 18F-Glu-Urea-Lys, a prostate-specific membrane antigen-based imaging agent for prostate cancer

Synthesis and positron emission tomography evaluation of 18F-Glu-Urea-Lys, a prostate-specific membrane antigen-based imaging agent for prostate cancer.

In recent years, single-photon emission computed tomography and positron emission tomography (PET) have also been used, in addition to computed tomography and magnetic resonance imaging, in targeting the diagnosis of prostate cancer. The aim of this study was to synthesize the prostate-specific membrane antigen (PSMA)-based imaging agent 2-{3-[1-Carboxy-5-(4-[18F] fluoro-benzoylamino)-pentyl]-ureido}-pentanedioic acid (18F-Glu-Urea-Lys, [18F]3) and to detect its PET imaging efficiency for high PSMA expression in prostate cancer. In this study, 18F-Glu-Urea-Lys was synthesized in two steps from the p-methoxybenzyl-protected Glu-Urea-Lys precursor using N-Hydroxysuccinimidyl-4-[18F] fluorobenzoate ([18F]SFB). PET imaging evaluation was conducted in nude mice using LNCaP (PSMA+), and PC-3, 231 and A549 (all PSMA-) xenograft models. The results indicated that 18F-Glu-Urea-Lys was produced in radiochemical yields of 28.7%. The radiochemical purity was 99.1% and the mean total synthesis time was 168 min. In nude mice models 18F-Glu-Urea-Lys clearly delineated PSMA+ LNCaP prostate tumor xenografts on PET imaging. At 4 h post-injection, the contrast agents were only observed in renal, liver, bladder and PSMA+ LNCaP tumors. The PSMA- tumor (PC-3, 231 and A549) was clear. In conclusion, 18F-Glu-Urea-Lys was found to be easily synthesized. This radiotracer demonstrated high tumor and low-to-normal tissue uptake, fast clearance from non-target tissues and retention in PSMA+ prostate tumor xenografts.

A high-affinity [18 F]-labeled phosphoramidate peptidomimetic PSMA-targeted inhibitor for PET imaging of prostate cancer

IntroductionIn this study, a structurally modified phosphoramidate scaffold, with improved prostate-specific membrane antigen (PSMA) avidity, stability and in vivo characteristics, as a PET imaging agent for prostate cancer (PCa), was prepared and evaluated. Methodsp-Fluorobenzoyl-aminohexanoate and 2-(3-hydroxypropyl)glycine were introduced into the PSMA-targeting scaffold yielding phosphoramidate 5. X-ray crystallography was performed on the PSMA/5 complex. [18F]5 was synthesized, and cell uptake and internalization studies were conducted in PSMA(+) LNCaP and CWR22Rv1 cells and PSMA(−) PC-3 cells. In vivo PET imaging and biodistribution studies were performed at 1 and 4h post injection in mice bearing CWR22Rv1 tumor, with or without blocking agent. ResultsThe crystallographic data showed interaction of the p-fluorobenzoyl group with an arene-binding cleft on the PSMA surface. In vitro studies revealed elevated uptake of [18F]5 in PSMA(+) cells (2.2% in CWR22Rv1 and 12.1% in LNCaP) compared to PSMA(−) cells (0.08%) at 4h. In vivo tumor uptake of 2.33% ID/g and tumor-to-blood ratio of 265:1 was observed at 4h. ConclusionsWe have successfully synthesized, radiolabeled and evaluated a new PSMA-targeted PET agent. The crystal structure of the PSMA/5 complex highlighted the interactions within the arene-binding cleft contributing to the overall complex stability. The high target uptake and rapid non-target clearance exhibited by [18F]5 in PSMA(+) xenografts substantiates its potential use for PET imaging of PCa. Advances in KnowledgeThe only FDA-approved imaging agent for PCa, Prostascint®, targets PSMA but suffers from inherent shortcomings. The data acquired in this manuscript confirmed that our new generation of [18F]-labeled PSMA inhibitor exhibited promising in vivo performance as a PET imaging agent for PCa and is well-positioned for subsequent clinical trials.Implications for Patient CareOur preliminary data demonstrate that this tracer possesses the required imaging characteristics to be sensitive and specific for PCa imaging in patients at all stages of the disease.

P1.05 - A ph 1 study of 2 different schedules of the PSMA-tubulysin small-molecule drug conjugate EC1169 in pts with rec Met Cast-Resist PC (MCRPC)

ABSTRACT Background: EC1169 is a conjugate of a prostate-specific membrane antigen (PSMA) targeting moiety linked to tubulysin B hydrazide (TubBH) that specifically binds to PSMA-expressing tumor cells to exert its anti-tumor effect in vivo. The PSMA “target” that binds EC1169 is overexpressed on a majority of prostate cancer (PCa) cells. TubBH, a member of the tubulysin class of anti-neoplastic agents, exerts an anti-tumor effect by inhibiting the polymerization of tubulin into microtubules, thus blocking spindle formation and arresting cells in metaphase. Xenograft studies demonstrated good EC1169's antitumor activity with complete remissions and cures observed in mice bearing PSMA-positive LNCaP and MDA PCa 2b tumors. 99mTc-EC0652 has a 99mTc binding moiety linked to a DUPA moiety, which binds to PSMA on the surface of target cells, and has displayed more sustained retention in PCa masses than any previously described PCa imaging agent. Materials and Methods: Key inclusion criteria are age ≥18 years, ECOG performance status 0–1, and adequate organ function. Patients must have failed prior or ongoing androgen-deprivation therapy, progressed on abiraterone or enzalutamide, and previously treated with a taxane unless contraindicated. All patients undergo a 99mTc-EC0652 scan, and EC1169 is IV bolus administered TIW or QW on wks 1, 2 of a 3-week cycle, with the continuous reassessment method (CRM) used for dose escalations. The primary study objective is to determine EC1169 MTD and recommended phase 2 dose. Secondary objectives include evaluating EC1169 safety, pharmacokinetic profiles, antitumor activity, and its correlation with PSMA expression as measured by 99mTc-EC0652. Results: Five patients had been enrolled into 5 dose levels, 3 in the TIW, and 2 in the QIW schedule. The number of cycles administered ranged from 1 to 4, with no dose delay or omission due to toxicity. No DLT was observed and only TEAEs of grade 1, were reported (e.g. dysgeusia, arthralgia and anorexia). One pt had SD for 4 cycles, and four pts are still on study. Conclusions: Dose escalation is ongoing, currently at 0.45 mg/m2 for both the TIW and QIW schedules. Updated data will be presented at the conference.

Development of targeted near-infrared imaging agents for prostate cancer.

Prostate cancer is the most common noncutaneous malignancy affecting men in North America. Radical prostatectomy remains a definitive treatment for prostate cancer. However, prostate surgeries are still performed "blindly" with the extent of tumor infiltration past the margins of the surgery only being determined postoperatively. An imaging modality that can be used during surgery is needed to help define the tumor margins. With its abundant expression in prostate cancer, prostate-specific membrane antigen (PSMA) is an ideal target for detection of prostate cancer. The purpose of this study was to develop PSMA-targeted near-infrared (NIR) optical imaging probes for intraoperative visualization of prostate cancer. We synthesized a high-affinity PSMA ligand (PSMA-1) with low molecular weight and further labeled it with commercially available NIR dyes IRDy800 and Cy5.5. PSMA-1 and PSMA-1-NIR conjugates had binding affinities better than the parent ligand Cys-CO-Glu. Selective binding was measured for each of the probes in both in vitro and in vivo studies using competitive binding and uptake studies. Interestingly, the results indicated that the pharmacokinetics of the probes was dependent of the fluorophore conjugated to the PSMA-1 ligand and varied widely. These data suggest that PSMA-targeted probes have the potential to be further developed as contrast agents for clinical intraoperative fluorescence-guided surgery.

PET imaging of prostate tumors with 18F-Al-NOTA-MATBBN.

Overexpression of the gastrin-releasing peptide receptor (GRPR) in prostate cancer provides a promising target for detection the disease. MATBBN is a new bombesin analog originating from the GRPR antagonists with a hydrophilic linker. In this study NOTA-conjugated MATBBN was labeled by the Al(18)F method and the potential of (18)F-Al-NOTA-MATBBN for prostate tumor PET imaging was also evaluated. NOTA-MATBBN was radiolabeled with (18) F using Al(18)F complexes. Partition coefficient, in vitro stability and GRPR binding affinity were also determined. PET studies were performed with (18)F-Al-NOTA-MATBBN in PC-3 tumor-bearing mice. (18)F-Al-NOTA-MATBBN can be produced within 30 min with a decay-corrected yield of 62.5 ± 2.1% and a radiochemical purity of >98%. The logP octanol-water value for the Al(18)F-labeled BBN analog was -2.40 ± 0.07 and the radiotracer was stable in phosphate-buffered saline and human serum for 2 h. The IC50 values of displacement for the (18)F-Al-NOTA-MATBBN with MATBBN was 126.9 ± 2.75 nm. The PC-3 tumors were clearly visible with high contrast after injection of the labeled peptide. At 60 min post-injection, the tumor uptakes for (18)F-Al-NOTA-MATBBN and (18)F-FDG were 4.59 ± 0.43 and 1.98 ± 0.35% injected dose/g, and tumor to muscle uptake radios for two tracers were 6.77 ± 1.10 and 1.78 ± 0.32, respectively. Dynamic PET revealed that (18) F-Al-NOTA-MATBBN was excreted mainly through the kidneys. GRPR-binding specificity was also demonstrated by reduced tumor uptake of (18)F-Al-NOTA-MATBBN after coinjection with excess unlabeled MATBBN peptide at 1 h post-injection. NOTA- MATBBN could be labeled rapidly with (18)F using one step method. (18)F-Al-NOTA-MATBBN may be a promising PET imaging agent for prostate cancer.

Abstract LB-90: DUPA-99mTc localizes to prostate cancer in men with locally advanced and metastatic disease.

Abstract Objectives: Currently, the absence of an effective prostate cancer targeted imaging agent limits the ability to correctly clinically stage prostate cancer. The conjugation of a high affinity PSMA-targeting ligand, 2-[3-(1, 3-dicarboxy propyl)-ureido] pentanedioic acid (DUPA) to technetium 99m (99mTc) has generated a new prostate cancer imaging agent termed DUPA-99mTc. The objective of this phase 0 clinical trial was to confirm the preclinical data demonstrating high affinity localization to human prostate cancer cells and tissues. Methods: Nine men with advanced and metastatic prostate cancer confirmed by CT scan and/or bone scan were enrolled in the Phase 0 trial to investigate both the biologic efficacy and toxicity of the DUPA-99mTc agent. Dosimetry studies of images, blood and urine at 5 and 20 mCi doses were obtained at baseline, 5 min, 1, 2, 4, 8 and 24 hours. Results: Nine men with documented prostate cancer were enrolled. Seven of the nine subjects were evaluable. One patient did not receive a full iv dose and another received poorly labeled DUPA-99mTc (70%). The remaining seven patients, who received DUPA-99mTc in excess of 95% labeled product, demonstrated localization to all cancerous areas seen on pre-enrollment images (CT and Bone Scans) plus additional lesions in several of the patients. Two men who had biopsy-confirmed locally recurrent prostate cancer had scans prior to resection, and tissue was monitored intra-operatively and ex-vivo to confirm the higher 99mTc counts in malignant tissue compared to normal tissue. No significant toxicity was demonstrated with administration of the DUPA-99mTc in any subject. Conclusions: DUPA-99mTc compound can be reliably administered to men with prostate cancer without toxicities and with equal or superior imaging compared to conventional CT and bone scans. A Phase I/II trial will be conducted to confirm the performance of this imaging agent in a larger patient population. Citation Format: Thomas A. Gardner, James W. Fletcher, Song-Chu Ko, Philip S. Low, Timothy L. Ratliff. DUPA-99mTc localizes to prostate cancer in men with locally advanced and metastatic disease. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-90. doi:10.1158/1538-7445.AM2013-LB-90

Inherently Multimodal Nanoparticle-Driven Tracking and Real-Time Delineation of Orthotopic Prostate Tumors and Micrometastases

Prostate cancer is the most common cancer among men and the second cause of male cancer-related deaths. There are currently three critical needs in prostate cancer imaging to personalize cancer treatment: (1) accurate intraprostatic imaging for multiple foci and extra-capsular extent; (2) monitoring local and systemic treatment response and predicting recurrence; and (3) more sensitive imaging of occult prostate cancer bone metastases. Recently, our lab developed porphysomes, inherently multimodal, all-organic nanoparticles with flexible and robust radiochemistry. Herein, we validate the first in vivo application of 64Cu-porphysomes in clinically relevant orthotopic prostate and bony metastatic cancer models. We demonstrate clear multimodal delineation of orthotopic tumors on both the macro- and the microscopic scales (using both PET and fluorescence) and sensitively detected small bony metastases (<2 mm). The unique and multifaceted properties of porphysomes offers a promising all-in-one prostate cancer imaging agent for tumor detection and treatment response/recurrence monitoring using both radionuclide- and photonic-based strategies.

2026 PHASE 0 TRIAL OF DUPA-99MTC IMAGING IN MEN WITH METASTATIC PROSTATE CANCER

You have accessJournal of UrologyImaging/Radiology: Uroradiology (I)1 Apr 20132026 PHASE 0 TRIAL OF DUPA-99MTC IMAGING IN MEN WITH METASTATIC PROSTATE CANCER Thomas Gardner, James Fletcher, Song-chu Ko, Mark Green, Gary Hutchins, Micheal Koch, Mark Tann, Phil Low, and Timothy Ratliff Thomas GardnerThomas Gardner Indianapolis, IN More articles by this author , James FletcherJames Fletcher Indianapolis, IN More articles by this author , Song-chu KoSong-chu Ko Lafayette, IN More articles by this author , Mark GreenMark Green Indianapolis, IN More articles by this author , Gary HutchinsGary Hutchins Indianapolis, IN More articles by this author , Micheal KochMicheal Koch Indianapolis, IN More articles by this author , Mark TannMark Tann Indianapolis, IN More articles by this author , Phil LowPhil Low West Lafayette, IN More articles by this author , and Timothy RatliffTimothy Ratliff West Lafayette, IN More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.2445AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Currently, no accurate imaging modality exists for staging metastatic prostate cancer. The Prostascint® scan, using a monoclonal antibody to the intracellular domain of the PSMA molecule, was thought to be an important staging tool, but its limited sensitivity and specificity have discouraged everyday use for patient care. Conjugation of a high affinity PSMA-targeting ligand, 2-[3-(1, 3-dicarboxy propyl)-ureido] pentanedioic acid (DUPA) to technetium 99m (99mTc) has generated a new prostate cancer imaging agent termed DUPA-99mTc. DUPA is a small molecule with high affinity for the same PSMA receptor targeted by Prostascint®, but the small molecule is attached to a chelator that can bind 99mTc, thereby rendering DUPA-99mTc an ideal imaging agent. Using animal models of human prostate cancer, studies demonstrated localization of DUPA-99mTc only to sites of prostate cancer. This Phase 0 trial was designed to confirm these findings in men with advanced prostate cancer. METHODS Nine men with advanced and metastatic prostate cancer confirmed by CT scan and/or bone scan were enrolled in the Phase 0 trial to investigate both the biologic efficacy and toxicity of the DUPA-99mTc agent. Dosimetry studies of images, blood and urine at 5 and 20 mCi doses were obtained at baseline, 5 min, 1, 2, 4, 8 and 24 hours. RESULTS Seven of nine subjects were evaluable. One patient did not receive a full iv dose and another received poorly labeled DUPA-99mTc (70%). The remaining seven patients, who received DUPA-99mTc in excess of 95% labeled product, demonstrated localization to all cancerous areas seen on pre-enrollment images (CT and Bone Scans) plus additional lesions in several of the patients. Two men who had biopsy-confirmed localized recurrent prostate cancer had scans prior to resection, and tissue was monitored intra-operatively and ex-vivo to confirm the higher 99mTc counts in malignant tissues compared to normal tissues. CONCLUSIONS DUPA-99mTc compound can be reliably administered to men with prostate cancer without toxicity and with equal or superior imaging compared to conventional CT and bone scans. A Phase I/II trial will be conducted to confirm the performance of this imaging agent in a larger patient population. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e832 Peer Review Report Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Thomas Gardner Indianapolis, IN More articles by this author James Fletcher Indianapolis, IN More articles by this author Song-chu Ko Lafayette, IN More articles by this author Mark Green Indianapolis, IN More articles by this author Gary Hutchins Indianapolis, IN More articles by this author Micheal Koch Indianapolis, IN More articles by this author Mark Tann Indianapolis, IN More articles by this author Phil Low West Lafayette, IN More articles by this author Timothy Ratliff West Lafayette, IN More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Abstract IA24: Molecular imaging agents for prostate cancer: Focus on PSMA

Abstract Although most clinical diagnostic imaging studies employ anatomic techniques such as computed tomography and magnetic resonance imaging, much of radiology research currently focuses on adapting these conventional methods to physiologic imaging as well as on introducing new techniques and probes for studying processes at the cellular and molecular levels in vivo, i.e. molecular imaging. Molecular imaging promises to provide new methods for the detection of minimal disease and support for personalized therapy. This summary will focus on experimental and near-term translational molecular imaging agents and methods for prostate cancer, with a focus on radiopharmaceuticals and optical agents, the former primarily for staging and the latter for surgical guidance. Citation Format: Martin G. Pomper. Molecular imaging agents for prostate cancer: Focus on PSMA [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr IA24.

18F-fluorocholine for prostate cancer imaging: a systematic review of the literature

Positron emission tomography (PET or combined PET-computed tomography (PET/CT)) allows the non-invasive interrogation of metabolic processes using radiolabeled probes. Altered choline metabolism has been noted as a characteristic of prostate cancer (PCa), and radiolabeled choline and choline analogs have been investigated as PET/CT imaging agents for prostate cancer; [(18)F]fluoromethyl-dimethyl-2-hydroxyethyl-ammonium ((18)F-FCH) shows particular promise as a PCa imaging agent given its favorable physical and pharmacokinetic properties. We conducted a systematic review of results to date with (18)F-FCH. As the tracer was first described by DeGrado in 2001, we limited our search from January 2001 to August 2011. In all, 37 studies including 1244 patients met the inclusion criteria. Studies included those detailing the radiosynthesis of (18)F-FCH, preclinical and early clinical dosimetry, and biodistribution (n=7); evaluation of local disease (n=6), nodal disease (n=5), bone metastases and castrate-resistant disease (n=7), biochemical recurrence (n=11), radiotherapy planning (n=7) and sources of false-positive studies (n=2); and some studies reported on multiple indications. Potential sources of variations in the studies affecting reported performance included case series size, variation in extent of disease at imaging (including Gleason grade, and PSA), selection of gold standards for comparison and variations in scan technique. On the basis of the review, we suggest potential scenarios where this metabolic imaging might be considered for further evaluation in clinical trials for guiding PCa management.

Development of an RNA-based SPECT/CT Imaging Agent for Prostate Cancer

Despite advances in screening approaches for prostate cancer, it is anticipated that 28,000 men will die of the disease this year in the United States alone. This highlights a need for more effective imaging technologies for staging, monitoring, and treatment planning of prostate cancer. ProstaScint is the only FDA-approved targeted-imaging agent for prostate cancer. However, its clinical utility is limited by low specificity and sensitivity. We describe a novel targeted imaging agent based on an RNA aptamer (A10-3.2) conjugated to a chelator (DOTA) housing an indium-111 radionuclide for SPECT/CT imaging.