Imaging of Nonprostate Cancers Using PSMA-Targeted Radiotracers: Rationale, Current State of the Field, and a Call to Arms

Fragomeni, Roberto A. Salas; Amir, Tali; Sheikhbahaei, Sara; Harvey, Susan C.; Javadi, Mehrbod S.; Solnes, Lilja B.; Kiess, Ana P.; Allaf, Mohamad E.; Pomper, Martin G.; Gorin, Michael A.; Rowe, Steven P.

doi:10.2967/jnumed.117.203570

Cited by 133 publications

(91 citation statements)

References 72 publications

(144 reference statements)

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“…In light of the growing availability of 68 Ga-or 18 F-labeled PSMA-targeted imaging agents (19)(20)(21)(22), the number of molecular imaging specialists that routinely interpret PET scans with these compounds outside controlled clinical trials is expanding (23). However, numerous studies have reported pitfalls in the reading of PSMA-targeted PET studies, including studies of Paget disease, sarcoidosis, or nervous tissue such as ganglia (7-10).…”

Section: Discussionmentioning

confidence: 99%

“…Identical Target Lesion Included by 4 Readers. The identical target lesion was included by all 4 readers in 58 of 125 (46.4%) instances, with the majority of those findings being either LN (26, 44.8%) or bone lesions (19,32.8%). In 29 (50%) of those 58 target lesions, all 4 readers designated the identical PSMA-RADS score, with another 17 lesions (29.3%) having agreement by 3 readers and the remaining 12 (20.7%) having agreement by 2 readers.…”

Section: Target Lesion-and Compartment-based Interobserver Agreementmentioning

confidence: 99%

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Interobserver Agreement for the Standardized Reporting System PSMA-RADS 1.0 on ¹⁸F-DCFPyL PET/CT Imaging

Werner

Bundschuh²,

Bundschuh³

et al. 2018

J Nucl Med

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Recently, the standardized reporting and data system for prostate-specific membrane antigen (PSMA)-targeted PET imaging studies, termed PSMA-RADS version 1.0, was introduced. We aimed to determine the interobserver agreement for applying PSMA-RADS to imaging interpretation of F-DCFPyL (2-(3-{1-carboxy-5-[(6-F-fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid) PET examinations in a prospective setting mimicking the typical clinical workflow at a prostate cancer referral center. Four readers (2 experienced readers (ERs,>3 y of PSMA-targeted PET interpretation experience) and 2 inexperienced readers (IRs, <1 y of experience)), who had all read the initial publication on PSMA-RADS 1.0, assessed 50 F-DCFPyL PET/CT studies independently. Per scan, a maximum of 5 target lesions was selected by the observers, and a PSMA-RADS score for every target lesion was recorded. No specific preexisting conditions were placed on the selection of the target lesions, although PSMA-RADS 1.0 suggests that readers focus on the most avid or largest lesions. An overall scan impression based on PSMA-RADS was indicated, and interobserver agreement rates on a target lesion-based, on an organ-based, and on an overall PSMA-RADS score-based level were computed. The number of target lesions identified by each observer was as follows: ER 1, 123; ER 2, 134; IR 1, 123; and IR 2, 120. Among those selected target lesions, 125 were chosen by at least 2 individual observers (all 4 readers selected the same target lesion in 58 of 125 [46.4%] instances, 3 readers in 40 of 125 [32%], and 2 observers in 27 of 125 [21.6%]). The interobserver agreement for PSMA-RADS scoring among identical target lesions was good (intraclass correlation coefficient [ICC] for 4, 3, and 2 identical target lesions, ≥0.60, respectively). For lymph nodes, an excellent interobserver agreement was derived (ICC, 0.79). The interobserver agreement for an overall scan impression based on PSMA-RADS was also excellent (ICC, 0.84), with a significant difference for ER (ICC, 0.97) vs. IR (ICC, 0.74) ( = 0.005). PSMA-RADS demonstrated a high concordance rate in this study, even among readers with different levels of experience. This finding suggests that PSMA-RADS can be effectively used for communication with clinicians and can be implemented in the collection of data for large prospective trials.

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Section: Discussionmentioning

confidence: 99%

Section: Target Lesion-and Compartment-based Interobserver Agreementmentioning

confidence: 99%

Interobserver Agreement for the Standardized Reporting System PSMA-RADS 1.0 on ¹⁸F-DCFPyL PET/CT Imaging

Werner

Bundschuh²,

Bundschuh³

et al. 2018

J Nucl Med

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“…Its expression is elevated with increasing PCa stage and grade making it an excellent biomarker for staging, metastasis detection, and image‐guided interventions . PSMA is also expressed on the neovasculature of other types of carcinomas such as breast and thyroid, making it an important biomarker in the larger scope of cancer research as well …”

Section: Methodsmentioning

confidence: 99%

“…[4,6] PSMA is also expressed on the neovasculature of other types of carcinomas such as breast and thyroid, making it an important biomarker in the larger scope of cancerresearch as well. [18,19] Elucidation of the structure of the PSMA binding site using protein crystallography led to the development of small molecule inhibitors which included amide, phosphonate, and urea substrate analogues. [6,20,21] Amongt he most effective of these was as mall molecule synthesized by ap eptidomimetic urea linkage of lysine to glutamic acid in place of the naturallyo ccurring peptidea mide substrate.…”

mentioning

confidence: 99%

Modular Synthesis of DOTA‐Metal‐Based PSMA‐Targeted Imaging Agents for MRI and PET of Prostate Cancer

Schmitthenner

Dobson

Jones

et al. 2019

Chemistry A European J

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A practical, convergent synthesis of prostate‐specific membrane antigen (PSMA) targeted imaging agents for MRI, PET, and SPECT of prostate cancer has been developed. In this approach, metals chelated to 1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid (DOTA) were placed on the side chains of lysine early in the synthesis to form imaging modules. These are coupled to targeting modules, in this case consisting of the PSMA‐binding urea DCL, bonded to an activated linker. The modular approach to targeted molecular imaging agents (TMIAs) offers distinct advantages. By chelating the MRI contrast metal Gd early, it doubles as a protecting group for DOTA. Standard coupling and deprotection steps may be utilized to assemble the modules into peptides, and the need for tri‐tert‐butyl protection of DOTA requiring removal by strong acid is averted. This enables mild conjugation of the imaging module to a wide variety of targeting agents in the final step. It was further discovered that two labile metals, La3+ or Ce3+, can be used as placeholders in DOTA during the synthesis, then transmetalated in mild acid by Cu2+, Ga3+, In3+, and Y3+, metals used in PET/SPECT. This enables the efficient synthesis of nonradioactive analogues of targeted molecular imaging agents that may be transported or stored until needed. A simple and mild two‐step transmetalation, involving de‐metalation in dilute acid, followed by rapid chelation of the radioactive metal, may be conveniently performed later at the clinic to provide the TMIAs for PET or SPECT.

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“…The most widely studied agent is the 68 Ga-labelled PSMA inhibitor Glu-NH-CO-NH-Lys(Ahx)-HBED-CC ( 68 Ga-PSMA) but in recent years 18 F-labelled ligands such as 2-(3-(1-carboxy-5-[(6-[ 18 F]fluoro-pyridine-3-carbonyl)-amino]-pentyl)-ureido)-pentanedioic acid ( 18 F-DCFPyL) have been developed which show advantages with respect to production amount, availability, clinical utility, and image resolution [3,4]. PSMA is also expressed by a variety of nonprostate cancers, often on the endothelium of tumor-associated neovasculature [5] and initial studies have explored the application of PSMA ligands in breast, lung, bladder, pancreatic and colorectal cancer, renal cell carcinoma and glioblastoma [6]. In a triple negative breast cancer xenograft the localization of PSMA was detected in the xenograft-associated endothelial cells as well as on the tumor cells [7].…”

Section: Introductionmentioning

confidence: 99%

High uptake of 68Ga-PSMA and 18F-DCFPyL in the peritumoral area of rat gliomas due to activated astrocytes

Oliveira

Stegmayr

Heinzel

et al. 2020

Preprint

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Background Recent studies reported on high uptake of the PSMA ligands [ 68 Ga]HBED-CC ( 68 Ga-PSMA) and 18 F-DCFPyL in cerebral gliomas. This study explores the regional uptake and cellular targets of 68 Ga-PSMA and 18 F-DCFPyL in three different rat glioma models. Methods F98, 9L or U87 rat gliomas were implanted into the brains of 38 rats. After 13 days of tumor growth, 68 Ga-PSMA (n=21) or 18 F-DCFPyL (n=17) were injected intravenously and animals were sacrificed 40 min later. Five animals for each tracer and tumor model were additionally investigated by micro-PET at 20-40 min postinjection. Cryosections of the tumor bearing brains were analyzed by ex vivo autoradiography and immunofluorescence staining for blood vessels, microglia, astrocytes and presence of PSMA. Blood-brain barrier (BBB) permeability was tested by coinjection of Evans blue dye (EBD). 68 Ga-PSMA uptake after restoration of BBB integrity by treatment with dexamethasone (Dex) was evaluated in four animals with U87 gliomas. Competition experiments using the PSMA-receptor inhibitor 2-(Phosphonomethyl)pentane-1,5-dioic acid (PMPA) were performed for both tracers in two animals each. Results Autoradiography demonstrated a strong 68 Ga-PSMA and 18 F-DCFPyL binding in the peritumoral area and moderate binding in the center of the tumors. PMPA administration led to complete inhibition of 68 Ga-PSMA and 18 F-DCFPyL binding in the peritumoral region. Restoration of BBB by Dex treatment reduced EBD extravasation but 68 Ga-PSMA binding remained unchanged. Expression of activated microglia (CD11b) was low in the intra- and peritumoral area but GFAP staining revealed strong activation of astrocytes in congruency to the tracer binding in the peritumoral area. All tumors were visualized in micro PET, showing a lower tumor/brain contrast with 68 Ga-PSMA than with 18 F-DCFPyL. Conclusions High uptake of 68 Ga-PSMA and 18 F-DCFPyL in the peritumoral area of all glioma models is presumably caused by activated astrocytes. This may represent a limitation for the clinical application of PSMA ligands in gliomas.

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Imaging of Nonprostate Cancers Using PSMA-Targeted Radiotracers: Rationale, Current State of the Field, and a Call to Arms

Cited by 133 publications

References 72 publications

Interobserver Agreement for the Standardized Reporting System PSMA-RADS 1.0 on ¹⁸F-DCFPyL PET/CT Imaging

Interobserver Agreement for the Standardized Reporting System PSMA-RADS 1.0 on ¹⁸F-DCFPyL PET/CT Imaging

Modular Synthesis of DOTA‐Metal‐Based PSMA‐Targeted Imaging Agents for MRI and PET of Prostate Cancer

High uptake of 68Ga-PSMA and 18F-DCFPyL in the peritumoral area of rat gliomas due to activated astrocytes

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Imaging of Nonprostate Cancers Using PSMA-Targeted Radiotracers: Rationale, Current State of the Field, and a Call to Arms

Cited by 133 publications

References 72 publications

Interobserver Agreement for the Standardized Reporting System PSMA-RADS 1.0 on 18F-DCFPyL PET/CT Imaging

Interobserver Agreement for the Standardized Reporting System PSMA-RADS 1.0 on 18F-DCFPyL PET/CT Imaging

Modular Synthesis of DOTA‐Metal‐Based PSMA‐Targeted Imaging Agents for MRI and PET of Prostate Cancer

High uptake of 68Ga-PSMA and 18F-DCFPyL in the peritumoral area of rat gliomas due to activated astrocytes

Contact Info

Product

Resources

About

Interobserver Agreement for the Standardized Reporting System PSMA-RADS 1.0 on ¹⁸F-DCFPyL PET/CT Imaging

Interobserver Agreement for the Standardized Reporting System PSMA-RADS 1.0 on ¹⁸F-DCFPyL PET/CT Imaging