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[(18)F]Fluorobenzoyllysinepentanedioic Acid Carbamates: New Scaffolds for Positron Emission Tomography (PET) Imaging of Prostate-Specific Membrane Antigen (PSMA).

ABSTRACT: Radiolabeled urea-based low-molecular weight inhibitors of the prostate-specific membrane antigen (PSMA) are under intense investigation as imaging and therapeutic agents for prostate and other cancers. In an effort to provide agents with less nontarget organ uptake than the ureas, we synthesized four (18)F-labeled inhibitors of PSMA based on carbamate scaffolds. 4-Bromo-2-[(18)F]fluorobenzoyllysineoxypentanedioic acid (OPA) carbamate [(18)F]23 and 4-iodo-2-[(18)F]fluorobenzoyllysine OPA carbamate [(18)F]24 in particular exhibited high target-selective uptake in PSMA+ PC3 PIP tumor xenografts, with tumor-to-kidney ratios of >1 by 4 h postinjection, an important benchmark. Because of its high tumor uptake (90% injected dose per gram of tissue at 2 h postinjection) and high tumor-to-organ ratios, [(18)F]23 is promising for clinical translation. Prolonged tumor-specific uptake demonstrated by [(18)F]24, which did not reach equilibrium during the 4 h study period, suggests carbamates as alternative scaffolds for mitigating dose to nontarget tissues.

SUBMITTER: Yang X

PROVIDER: S-EPMC4856055 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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[(18)F]Fluorobenzoyllysinepentanedioic Acid Carbamates: New Scaffolds for Positron Emission Tomography (PET) Imaging of Prostate-Specific Membrane Antigen (PSMA).

Yang Xing X Mease Ronnie C RC Pullambhatla Mrudula M Lisok Ala A Chen Ying Y Foss Catherine A CA Wang Yuchuan Y Shallal Hassan H Edelman Hannah H Hoye Adam T AT Attardo Giorgio G Nimmagadda Sridhar S Pomper Martin G MG

Journal of medicinal chemistry 20151216 1

Radiolabeled urea-based low-molecular weight inhibitors of the prostate-specific membrane antigen (PSMA) are under intense investigation as imaging and therapeutic agents for prostate and other cancers. In an effort to provide agents with less nontarget organ uptake than the ureas, we synthesized four (18)F-labeled inhibitors of PSMA based on carbamate scaffolds. 4-Bromo-2-[(18)F]fluorobenzoyllysineoxypentanedioic acid (OPA) carbamate [(18)F]23 and 4-iodo-2-[(18)F]fluorobenzoyllysine OPA carbama ...[more]

PMID: 26629713

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Project description:PurposeProstate specific membrane antigen targeted 18F-DCFPyL positron emission tomography/computerized tomography may offer superior image quality and sensitivity for the detection of biochemically recurrent prostate cancer. We examined the association of Gleason sum, serum prostate specific antigen and prostate specific antigen doubling time with any detectable and pelvic confined disease in patients with biochemically recurrent prostate cancer.Materials and methodsData from 108 patients with biochemically recurrent prostate cancer after radical prostatectomy who underwent prostate specific membrane antigen targeted 18F-DCFPyL positron emission tomography/computerized tomography were analyzed. Data were collected on positive positron emission tomography findings as well as pelvic confined disease. Associations between Gleason sum, prostate specific antigen and prostate specific antigen doubling time were retrospectively explored.ResultsSerum prostate specific antigen was associated with positive prostate specific membrane antigen targeted imaging as continuous (OR 3.08, 95% CI 1.60-7.95, p=0.005) and categorical values (ie prostate specific antigen greater than 2.0 to 5.0 vs 0.5 ng/ml or less, OR 16.92, 95% CI 3.13-315.81, p=0.008). No relationship between Gleason sum or prostate specific antigen doubling time with overall positive imaging was observed. Patients with a prostate specific antigen greater than 2.0 to 5.0 ng/ml were significantly less likely to be diagnosed with pelvic confined disease compared with the 0.5 ng/ml or less subgroup (OR 0.21, 95% CI 0.06-0.69, p=0.013). A prostate specific antigen doubling time of 9 months or more (OR 4.20, 95% CI 1.57-11.89, p=0.005) or prostate specific antigen doubling time of 12 months or more (OR 3.03, 95% CI 1.12-8.76, p=0.033) was significantly associated with pelvic confined disease. No relationship between Gleason sum and pelvic confined disease was observed.ConclusionsAbsolute prostate specific antigen was positively associated with the presence of findings on prostate specific membrane antigen targeted imaging and negatively associated with pelvic confined disease. Prostate specific antigen doubling time did not predict for overall disease detection, but long prostate specific antigen doubling times were associated with pelvic confined prostate cancer.

Project description:PurposeThis study aimed to evaluate the clinical utility of 18F-PSMA-1007 positron emission tomography (PSMA PET)/magnetic resonance imaging (MRI) imaging in patients with suspected or defined prostate cancer.MethodsIn the pilot study, we retrospectively investigated 62 patients who underwent PSMA-PET/MRI for suspected or defined PCa between June 2019 and June 2020. Patients were grouped into three subgroups: (1) suspected PCa without histological evidence, (2) primary PCa, (3) biochemical recurrent prostate cancer (BRPCa). Two nuclear physicians independently interpreted the results of PSMA-PET/MRI. Management strategies before PSMA-PET/MRI were retrospectively reported, and the management strategy was re-evaluated for each patient considering the PSMA-PET/MRI result. The changes in strategies were recorded. Besides, the correlation between prostate specific antigen (PSA) level and management changes was also accessed by Fisher exact test, and two-side p < 0.05 was assumed as statistical significance.ResultsThere were 28 patients in the suspected PCa group (group 1), 12 in the primary PCa group (group 2), and 22 in the BRPCa group (group 3). Overall, the intended decisions were changed in 26 (41.9%) of 62 patients after PSMA-PET/MRI, including 11/28 (39.3%) in suspected PCa group, 1/12 (8.4%) in primary PCa group, and 14/24 (63.6%) in BCR group. In group 1, the main impact on subsequent management included decreased active surveillance (from 20 to 9) and increased prostate biopsy (from 8 to 19). PSA levels were not significantly associated with management changes in suspected PCa patients (p = 0.865). In group 2, the main impact on subsequent management included decreased radical surgery (from 8 to 7), and multimodal therapy appearance (n = 1). Only in the category of PSA levels of ≥20 ng/ml, the management of primary PCa was changed. In group 3, the main impact on subsequent management included decreased salvage radiotherapy (from 5 to 2), increased systemic therapy (from 6 to 7), and increased multimodal therapy (from 11 to 13). The highest proportion of management changes occurred in BCR patients with 0.5≤PSA<1 ng/ml.ConclusionFrom our preliminary experience, PSMA-PET/MRI may be a valued tool for defining PCa lesions and changing management. The biggest impact of management intent was in patients with BRPCa, especially in patients with 0.5≤PSA<1 ng/ml. However, further studies are needed to confirm our pilot findings.

Project description:Purpose:Stereotactic ablative radiation therapy (SABR) for oligometastatic prostate cancer (OMPC) may improve clinical outcomes, but current challenges in intrafraction tracking of multiple small targets limits treatment accuracy. A biology-guided radiation therapy (BgRT) delivery system incorporating positron emission tomography (PET) detectors is being developed to use radiotracer uptake as a biologic fiducial for intrafraction tumor tracking to improve geometric accuracy. This study simulates prostate-specific membrane antigen (PSMA)-directed BgRT using a cohort from our phase II randomized trial of SABR in men with recurrent hormone sensitive OMPC and compares dose distributions to clinical SABR (CSABR). Methods and Materials:A research treatment planning system (RTPS) was used to replan 15 patients imaged with PSMA-targeted 18F-DCFPyL PET/computed tomography and previously treated with CSABR using conventional linear accelerators (linacs). The RTPS models a prototype ring-mounted linac incorporating PET and kilo-voltage computed tomography imaging subsystems and can be used to optimize BgRT plans, as well as research SABR (RSABR) plans, which use the prototype linac without radiotracer guidance. CSABR, RSABR, and BgRT plans were compared in terms of maximum planning target volume (PTV) dose (Dmax), mean dose to proximal organs at risk (DOAR), conformity index, as well as voxel-wise correlation of dose with PET specific uptake values to investigate possible dose-painting effects. Results:RSABR and BgRT plans resulted in mean ± standard deviation increases in Dmax of 4 ± 11% (P = .21) and 18 ± 15% (P < .001) and reductions in DOAR of -20 ± 19% (P <.001) and -10 ± 19% (P = .02) compared with CSABR. Similar target coverage was maintained with conformity indices of 0.81 ± 0.04 (P < .001) and 0.72 ± 0.08 (P = .44) for RSABR and BgRT compared with 0.74 ± 0.08 for CSABR. Dose and log (specific uptake values) had Pearson correlation coefficients of 0.10 (CSABR), 0.16 (RSABR), and 0.31 (BgRT). Conclusions:BgRT plans provided similar PTV coverage and conformity compared with CSABR while incorporating underlying PET activity. These results demonstrate feasibility of BgRT optimization enabling online PSMA-targeted, PET-based tracked dose delivery for OMPC.

Dataset Information

[(18)F]Fluorobenzoyllysinepentanedioic Acid Carbamates: New Scaffolds for Positron Emission Tomography (PET) Imaging of Prostate-Specific Membrane Antigen (PSMA).

Publications

[(18)F]Fluorobenzoyllysinepentanedioic Acid Carbamates: New Scaffolds for Positron Emission Tomography (PET) Imaging of Prostate-Specific Membrane Antigen (PSMA).

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