ABSTRACT
The authors define molecular imaging, according to the Society of Nuclear Medicine and Molecular Imaging, as the visualization, characterization, and measurement of biological processes at the molecular and cellular levels in humans and other living systems. Although practiced for many years clinically in nuclear medicine, expansion to other imaging modalities began roughly 25 years ago and has accelerated since. That acceleration derives from the continual appearance of new and highly relevant animal models of human disease, increasingly sensitive imaging devices, high-throughput methods to discover and optimize affinity agents to key cellular targets, new ways to manipulate genetic material, and expanded use of cloud computing. Greater interest by scientists in allied fields, such as chemistry, biomedical engineering, and immunology, as well as increased attention by the pharmaceutical industry, have likewise contributed to the boom in activity in recent years. Whereas researchers and clinicians have applied molecular imaging to a variety of physiologic processes and disease states, here, the authors focus on oncology, arguably where it has made its greatest impact. The main purpose of imaging in oncology is early detection to enable interception if not prevention of full-blown disease, such as the appearance of metastases. Because biochemical changes occur before changes in anatomy, molecular imaging-particularly when combined with liquid biopsy for screening purposes-promises especially early localization of disease for optimum management. Here, the authors introduce the ways and indications in which molecular imaging can be undertaken, the tools used and under development, and near-term challenges and opportunities in oncology.
Subject(s)
Medical Oncology , Molecular Imaging , Animals , Humans , Magnetic Resonance Imaging , Molecular Imaging/methods , Positron-Emission TomographyABSTRACT
Aluminum fluoride (AlF) complexes have been used over the past decade to incorporate [18F]fluoride into large biomolecules in a highly selective fashion by using relatively facile conditions. However, despite their widespread usage, there are a large number of variations in the reaction conditions, without a definitive discussion provided on the mechanism to understand how these changes would alter the end result. Herein, we report a detailed mechanistic investigation of the reaction, using a mixture of theoretical studies, fluorine-19 and fluorine-18 chemistry, and the consequences it has on the efficient clinical translation of AlF-containing imaging agents.
Subject(s)
Aluminum Compounds , Chelating Agents , Fluorides , Fluorides/chemistry , Aluminum Compounds/chemistry , Chelating Agents/chemistry , Chelating Agents/chemical synthesis , Fluorine Radioisotopes/chemistry , Molecular StructureABSTRACT
OBJECTIVES: PET-based radiomic metrics are increasingly utilized as predictive image biomarkers. However, the repeatability of radiomic features on PET has not been assessed in a test-retest setting. The prostate-specific membrane antigen-targeted compound 18 F-DCFPyL is a high-affinity, high-contrast PET agent that we utilized in a test-retest cohort of men with metastatic prostate cancer (PC). METHODS: Data of 21 patients enrolled in a prospective clinical trial with histologically proven PC underwent two 18 F-DCFPyL PET scans within 7 days, using identical acquisition and reconstruction parameters. Sites of disease were segmented and a set of 29 different radiomic parameters were assessed on both scans. We determined repeatability of quantification by using Pearson's correlations, within-subject coefficient of variation (wCOV), and Bland-Altman analysis. RESULTS: In total, 230 lesions (177 bone, 38 lymph nodes, 15 others) were assessed on both scans. For all investigated radiomic features, a broad range of inter-scan correlation was found (r, 0.07-0.95), with acceptable reproducibility for entropy and homogeneity (wCOV, 16.0% and 12.7%, respectively). On Bland-Altman analysis, no systematic increase or decrease between the scans was observed for either parameter (±1.96 SD: 1.07/-1.30, 0.23/-0.18, respectively). The remaining 27 tested radiomic metrics, however, achieved unacceptable high wCOV (≥21.7%). CONCLUSION: Many common radiomic features derived from a test-retest PET study had poor repeatability. Only Entropy and homogeneity achieved good repeatability, supporting the notion that those image biomarkers may be incorporated in future clinical trials. Those radiomic features based on high frequency aspects of images appear to lack the repeatability on PET to justify further study.
Subject(s)
Positron Emission Tomography Computed Tomography , Prostatic Neoplasms , Male , Humans , Positron Emission Tomography Computed Tomography/methods , Prospective Studies , Reproducibility of Results , Positron-Emission Tomography , Prostatic Neoplasms/diagnostic imaging , Prostatic Neoplasms/pathology , Contrast MediaABSTRACT
OBJECTIVES: We evaluated 18 F-DCFPyL test-retest repeatability of uptake in normal organs. METHODS: Twenty-two prostate cancer (PC) patients underwent two 18 F-DCFPyL PET scans within 7 days within a prospective clinical trial (NCT03793543). In both PET scans, uptake in normal organs (kidneys, spleen, liver, and salivary and lacrimal glands) was quantified. Repeatability was determined by using within-subject coefficient of variation (wCOV), with lower values indicating improved repeatability. RESULTS: For SUVmean , repeatability was high for kidneys, spleen, liver, and parotid glands (wCOV, range: 9.0%-14.3%) and lower for lacrimal (23.9%) and submandibular glands (12.4%). For SUVmax , however, the lacrimal (14.4%) and submandibular glands (6.9%) achieved higher repeatability, while for large organs (kidneys, liver, spleen, and parotid glands), repeatability was low (range: 14.1%-45.2%). CONCLUSION: We found acceptable repeatability of uptake on 18 F-DCFPyL PET for normal organs, in particular for SUVmean in the liver or parotid glands. This may have implications for both PSMA-targeted imaging and treatment, as patient selection for radioligand therapy and standardized frameworks for scan interpretation (PROMISE, E-PSMA) rely on uptake in those reference organs.
Subject(s)
Positron Emission Tomography Computed Tomography , Prostatic Neoplasms , Humans , Male , Lysine , Positron Emission Tomography Computed Tomography/methods , Prospective Studies , Prostatic Neoplasms/diagnostic imaging , UreaABSTRACT
Here, we describe and assess the potential of 14 newly synthesized imidazole-4,5-dicarboxyamides (I45DCs) for pH and perfusion imaging. A number of these aromatic compounds possess large labile proton chemical shifts (up to 7.7 ppm from water) because of their intramolecular hydrogen bonds and a second labile proton to allow for chemical exchange saturation transfer (CEST) signal ratio-based pH measurements. We have found that the contrast produced is strong for a wide range of substitutions and that the inflection points in the CEST signal ratio versus pH plots used to generate concentration-independent pH maps can be adjusted based on these subsitutions to tune the pH range that can be measured. These I45DC CEST agents have advantages over the triiodobenzenes currently employed for tumor and kidney pH mapping, both preclinically and in initial human studies. Finally, as CEST MRI combined with exogenous contrast has the potential to detect functional changes in the kidneys, we evaluated our highest performing anionic compound (I45DC-diGlu) on a unilateral urinary obstruction mouse model and observed lower contrast uptake in the obstructed kidney compared with the unobstructed kidney and that the unobstructed kidney displayed a pH of ~ 6.5 while the obstructed kidney had elevated pH and an increased range in pH values. Based on this, we conclude that the I45DCs have excellent imaging properties and hold promise for a variety of medical imaging applications, particularly renal imaging.
Subject(s)
Contrast Media , Protons , Mice , Animals , Humans , Hydrogen-Ion Concentration , Contrast Media/chemistry , Phantoms, Imaging , Magnetic Resonance Imaging/methods , Imidazoles , Perfusion ImagingABSTRACT
BACKGROUND: Quantification of [68 Ga]-labeled PSMA PET predicts response in patients with prostate cancer (PC) who undergo PSMA-targeted radioligand therapy (RLT). Given the increasing use [18F]-labeled radiotracers, we aimed to determine whether the uptake derived from [18F]PSMA-1007 PET can also identify responders and to assess its prognostic value relative to established clinical parameters. METHODS: We retrospectively analyzed 103 patients with metastatic, castration-resistant PC who were treated with [177Lu]Lu-PSMA I&T. We calculated SUVmean, SUVmax, PSMA-avid tumor volume (TV), and total lesion PSMA (defined as PSMA-TV*SUVmean) on pre-therapeutic [18F]PSMA-1007 PET. Laboratory values for hemoglobin, C-reactive protein (CRP), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), and alkaline phosphatase (AP) were also collected prior to RLT. We performed univariable Cox regression followed by multivariable and Kaplan-Meier analyses with overall survival (OS) serving as endpoint. Last, we also computed a risk factor (RF) model including all items reaching significance on multivariable analysis to determine whether an increasing number of RFs can improve risk stratification. RESULTS: A total of 48 patients died and median OS was 16 months. On univariable Cox regression, SUVmean, CRP, LDH, hemoglobin, and the presence of liver metastases were significantly associated with OS. On multivariable Cox regression, the following significant prognostic factors for OS were identified: SUVmean (per unit, HR, 0.91; P = 0.04), the presence of liver metastases (HR, 2.37; P = 0.03), CRP (per mg/dl, HR, 1.13; P = 0.003), and hemoglobin (per g/dl, HR, 0.76; P < 0.01). Kaplan-Meier analysis showed significant separation between patients with a SUVmean below or above a median SUVmean of 9.4 (9 vs 19 months, HR 0.57; P = 0.03). Of note, patients with only one RF (median OS not reached) showed longest survival compared to patients with two (11 months; HR 2.43 95% CI 1.07-5.49, P = 0.02) or more than two RFs (7 months; HR 3.37 95% CI 1.62-7.03, P < 0.001). CONCLUSION: A lower SUVmean derived from [18F]PSMA-1007, higher CRP, lower hemoglobin, and the presence of liver metastases are associated with reduced OS in patients undergoing RLT. An early RF model also demonstrated that an increasing number of those factors is linked to worse outcome, thereby emphasizing the importance of clinical and imaging parameters for adequate risk stratification.
Subject(s)
Prostate-Specific Antigen , Prostatic Neoplasms, Castration-Resistant , Male , Humans , Treatment Outcome , Retrospective Studies , Prostate-Specific Antigen/therapeutic use , Prostatic Neoplasms, Castration-Resistant/diagnostic imaging , Prostatic Neoplasms, Castration-Resistant/radiotherapy , Prostatic Neoplasms, Castration-Resistant/drug therapy , Dipeptides/therapeutic use , Positron-Emission Tomography , Heterocyclic Compounds, 1-Ring/therapeutic use , Lutetium/therapeutic useABSTRACT
PURPOSE: We report findings from the first-in-human study of [11C]MDTC, a radiotracer developed to image the cannabinoid receptor type 2 (CB2R) with positron emission tomography (PET). METHODS: Ten healthy adults were imaged according to a 90-min dynamic PET protocol after bolus intravenous injection of [11C]MDTC. Five participants also completed a second [11C]MDTC PET scan to assess test-retest reproducibility of receptor-binding outcomes. The kinetic behavior of [11C]MDTC in human brain was evaluated using tissue compartmental modeling. Four additional healthy adults completed whole-body [11C]MDTC PET/CT to calculate organ doses and the whole-body effective dose. RESULTS: [11C]MDTC brain PET and [11C]MDTC whole-body PET/CT was well-tolerated. A murine study found evidence of brain-penetrant radiometabolites. The model of choice for fitting the time activity curves (TACs) across brain regions of interest was a three-tissue compartment model that includes a separate input function and compartment for the brain-penetrant metabolites. Regional distribution volume (VT) values were low, indicating low CB2R expression in the brain. Test-retest reliability of VT demonstrated a mean absolute variability of 9.91%. The measured effective dose of [11C]MDTC was 5.29 µSv/MBq. CONCLUSION: These data demonstrate the safety and pharmacokinetic behavior of [11C]MDTC with PET in healthy human brain. Future studies identifying radiometabolites of [11C]MDTC are recommended before applying [11C]MDTC PET to assess the high expression of the CB2R by activated microglia in human brain.
Subject(s)
Positron Emission Tomography Computed Tomography , Radiopharmaceuticals , Adult , Humans , Animals , Mice , Reproducibility of Results , Radiopharmaceuticals/pharmacokinetics , Positron-Emission Tomography/methods , Brain/diagnostic imaging , Brain/metabolism , Receptors, Cannabinoid/metabolismABSTRACT
PURPOSE: Soluble epoxide hydrolase (sEH) is an enzyme that shapes immune signaling through its role in maintaining the homeostasis of polyunsaturated fatty acids and their related byproducts. [18F]FNDP is a radiotracer developed for use with positron emission tomography (PET) to image sEH, which has been applied to imaging sEH in the brains of healthy individuals. Here, we report the test-retest repeatability of [18F]FNDP brain PET binding and [18F]FNDP whole-body dosimetry in healthy individuals. METHODS: Seven healthy adults (4 men, 3 women, ages 40.1 ± 4.6 years) completed [18F]FNDP brain PET on two occasions within a period of 14 days in a test-retest study design. [18F]FNDP regional total distribution volume (VT) values were derived from modeling time-activity data with a metabolite-corrected arterial input function. Test-retest variability, mean absolute deviation, and intraclass correlation coefficient (ICC) were investigated. Six other healthy adults (3 men, 3 women, ages 46.0 ± 7.0 years) underwent [18F]FNDP PET/CT for whole-body dosimetry, which was acquired over 4.5 h, starting immediately after radiotracer administration. Organ-absorbed doses and the effective dose were then estimated. RESULTS: The mean test-retest difference in regional VT (ΔVT) was 0.82 ± 5.17%. The mean absolute difference in regional VT was 4.01 ± 3.33%. The ICC across different brain regions ranged from 0.92 to 0.99. The organs with the greatest radiation-absorbed doses included the gallbladder (0.081 ± 0.024 mSv/MBq), followed by liver (0.077 ± 0.018 mSv/MBq) and kidneys (0.063 ± 0.006 mSv/MBq). The effective dose was 0.020 ± 0.003 mSv/MBq. CONCLUSION: These data support a favorable test-retest repeatability of [18F]FNDP brain PET regional VT. The radiation dose to humans from each [18F]FNDP PET scan is similar to that of other 18F-based PET radiotracers.
Subject(s)
Positron Emission Tomography Computed Tomography , Positron-Emission Tomography , Male , Adult , Humans , Female , Positron-Emission Tomography/methods , Radiometry , Radiation Dosage , NeuroimagingABSTRACT
Prostate-specific membrane antigen (PSMA)-targeted positron emission tomography (PET) is rapidly becoming widely accepted as the standard-of-care for imaging of men with prostate cancer. Labeled indications for regulatoryapproved agents include primary staging and recurrent disease in men at risk of metastases. The first commercial PSMA PET agent to become available was 18F-DCFPyL (piflufolastat F 18), a radiofluorinated small molecule with high-affinity for PSMA. The regulatory approval of 18F-DCFPyL hinged upon two key, multi-center, registration trials, OSPREY (patient population: highrisk primary staging) and CONDOR (patient population: biochemical recurrence). In this manuscript, we will (1) review key findings from the OSPREY and CONDOR trials, (2) discuss the clinical acquisition protocol we use for 18F-DCFPyL PET scanning, (3) present information on important pearls and pitfalls, (4) provide an overview of the PSMA reporting and data system (PSMA-RADS) interpretive framework, and (5) posit important future directions for research in PSMA PET. Our overall goal is to provide a brief introduction for practices and academic groups that are adopting 18F-DCFPyL PET scans for use in their patients with prostate cancer.
Subject(s)
Positron Emission Tomography Computed Tomography , Prostatic Neoplasms , Male , Humans , Positron Emission Tomography Computed Tomography/methods , Positron-Emission Tomography , Prostatic Neoplasms/diagnostic imaging , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/pathology , LysineABSTRACT
Prostate-specific membrane antigen (PSMA)-based low-molecular-weight agents using beta(ß)-particle-emitting radiopharmaceuticals is a new treatment paradigm for patients with metastatic castration-resistant prostate cancer. Although results have been encouraging, there is a need to improve the tumor residence time of current PSMA-based radiotherapeutics. Albumin-binding moieties have been used strategically to enhance the tumor uptake and retention of existing PSMA-based investigational agents. Previously, we developed a series of PSMA-based, ß-particle-emitting, low-molecular-weight compounds. From this series, 177Lu-L1 was selected as the lead agent because of its reduced off-target radiotoxicity in preclinical studies. The ligand L1 contains a PSMA-targeting Lys-Glu urea moiety with an N-bromobenzyl substituent in the ε-amino group of Lys. Here, we structurally modified 177Lu-L1 to improve tumor targeting using two known albumin-binding moieties, 4-(p-iodophenyl) butyric acid moiety (IPBA) and ibuprofen (IBU), and evaluated the effects of linker length and composition. Six structurally related PSMA-targeting ligands (Alb-L1-Alb-L6) were synthesized based on the structure of 177Lu-L1. The ligands were assessed for in vitro binding affinity and were radiolabeled with 177Lu following standard protocols. All 177Lu-labeled analogs were studied in cell uptake and selected cell efficacy studies. In vivo pharmacokinetics were investigated by conducting tissue biodistribution studies for 177Lu-Alb-L2-177Lu-Alb-L6 (2 h, 24 h, 72 h, and 192 h) in male NSG mice bearing human PSMA+ PC3 PIP and PSMA- PC3 flu xenografts. Preliminary therapeutic ratios of the agents were estimated from the area under the curve (AUC0-192h) of the tumors, blood, and kidney uptake values. Compounds were obtained in >98% radiochemical yields and >99% purity. PSMA inhibition constants (Kis) of the ligands were in the ≤10 nM range. The long-linker-based agents, 177Lu-Alb-L4 and 177Lu-Alb-L5, displayed significantly higher tumor uptake and retention (p < 0.001) than the short-linker-bearing 177Lu-Alb-L2 and 177Lu-Alb-L3 and a long polyethylene glycol (PEG) linker-bearing agent, 177Lu-Alb-L6. The area under the curve (AUC0-192h) of the PSMA+ PC3 PIP tumor uptake of 177Lu-Alb-L4 and 177Lu-Alb-L5 were >4-fold higher than 177Lu-Alb-L2, 177Lu-Alb-L3, and 177Lu-Alb-L6, respectively. Also, the PSMA+ PIP tumor uptake (AUC0-192h) of 177Lu-Alb-L2 and 177Lu-Alb-L3 was ~1.5-fold higher than 177Lu-Alb-L6. However, the lowest blood AUC0-192h and kidney AUC0-192h were associated with 177Lu-Alb-L6 from the series. Consequently, 177Lu-Alb-L6 displayed the highest ratios of AUC(tumor)-to-AUC(blood) and AUC(tumor)-to-AUC(kidney) values from the series. Among the other agents, 177Lu-Alb-L4 demonstrated a nearly similar ratio of AUC(tumor)-to-AUC(blood) as 177Lu-Alb-L6. The tumor-to-blood ratio was the dose-limiting therapeutic ratio for all of the compounds. Conclusions: 177Lu-Alb-L4 and 177Lu-Alb-L6 showed high tumor uptake in PSMA+ tumors and tumor-to-blood ratios. The data suggest that linker length and composition can be modulated to generate an optimized therapeutic agent.
Subject(s)
Albumins , Beta Particles , Humans , Male , Animals , Mice , Ligands , Tissue Distribution , Butyric AcidABSTRACT
Background: Mediating glucose absorption in the small intestine and renal clearance, sodium glucose cotransporters (SGLTs) have emerged as an attractive therapeutic target in diabetic patients. A substantial fraction of patients, however, only achieve inadequate glycemic control. Thus, we aimed to assess the potential of the SGLT-targeting PET radiotracer alpha-methyl-4-deoxy-4-[18F]fluoro-D-glucopyranoside ([18F]Me4FDG) as a noninvasive intestinal and renal biomarker of SGLT-mediated glucose transport. Methods: We investigated healthy rats using a dedicated small animal PET system. Dynamic imaging was conducted after administration of the reference radiotracer 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG), or the SGLT-targeting agent, [18F]Me4FDG either directly into the digestive tract (for assessing intestinal absorption) or via the tail vein (for evaluating kidney excretion). To confirm the specificity of [18F]Me4FDG and responsiveness to treatment, a subset of animals was also pretreated with the SGLT inhibitor phlorizin. In this regard, an intraintestinal route of administration was used to assess tracer absorption in the digestive tract, while for renal assessment, phlorizin was injected intravenously (IV). Results: Serving as reference, intestinal administration of [18F]FDG led to slow absorption with retention of 89.2 ± 3.5% of administered radioactivity at 15 min. [18F]Me4FDG, however, was rapidly absorbed into the blood and cleared from the intestine within 15 min, leading to markedly lower tracer retention of 18.5 ± 1.2% (P < 0.0001). Intraintestinal phlorizin led to marked increase of [18F]Me4FDG uptake (15 min, 99.9 ± 4.7%; P < 0.0001 vs. untreated controls), supporting the notion that this PET agent can measure adequate SGLT inhibition in the digestive tract. In the kidneys, radiotracer was also sensitive to SGLT inhibition. After IV injection, [18F]Me4FDG reabsorption in the renal cortex was significantly suppressed by phlorizin when compared to untreated animals (%ID/g at 60 min, 0.42 ± 0.10 vs. untreated controls, 1.20 ± 0.03; P < 0.0001). Conclusion: As a noninvasive read-out of the concurrent SGLT expression in both the digestive tract and the renal cortex, [18F]Me4FDG PET may serve as a surrogate marker for treatment response to SGLT inhibition. As such, [18F]Me4FDG may enable improvement in glycemic control in diabetes by PET-based monitoring strategies.
Subject(s)
Fluorodeoxyglucose F18 , Positron-Emission Tomography , Animals , Glucose/metabolism , Glucosides , Phlorhizin , Positron-Emission Tomography/methods , Rats , Sodium/metabolism , Sodium-Glucose Transport Proteins/metabolismABSTRACT
Objectives: In patients with prostate cancer (PC) receiving prostate-specific membrane antigen- (PSMA-) targeted radioligand therapy (RLT), higher baseline standardized uptake values (SUVs) are linked to improved outcome. Thus, readers deciding on RLT must have certainty on the repeatability of PSMA uptake metrics. As such, we aimed to evaluate the test-retest repeatability of lesion uptake in a large cohort of patients imaged with 18F-DCFPyL. Methods: In this prospective, IRB-approved trial (NCT03793543), 21 patients with history of histologically proven PC underwent two 18F-DCFPyL PET/CTs within 7 days (mean 3.7, range 1 to 7 days). Lesions in the bone, lymph nodes (LN), and other organs were manually segmented on both scans, and uptake parameters were assessed (maximum (SUVmax) and mean (SUVmean) SUVs), PSMA-tumor volume (PSMA-TV), and total lesion PSMA (TL-PSMA, defined as PSMA - TV × SUVmean)). Repeatability was determined using Pearson's correlations, within-subject coefficient of variation (wCOV), and Bland-Altman analysis. Results: In total, 230 pairs of lesions (177 bone, 38 LN, and 15 other) were delineated, demonstrating a wide range of SUVmax (1.5-80.5) and SUVmean (1.4-24.8). Including all sites of suspected disease, SUVs had a strong interscan correlation (R 2 ≥ 0.99), with high repeatability for SUVmean and SUVmax (wCOV, 7.3% and 12.1%, respectively). High SUVs showed significantly improved wCOV relative to lower SUVs (P < 0.0001), indicating that high SUVs are more repeatable, relative to the magnitude of the underlying SUV. Repeatability for PSMA-TV and TL-PSMA, however, was low (wCOV ≥ 23.5%). Across all metrics for LN and bone lesions, interscan correlation was again strong (R 2 ≥ 0.98). Moreover, LN-based SUVmean also achieved the best wCOV (3.8%), which was significantly reduced when compared to osseous lesions (7.8%, P < 0.0001). This was also noted for SUVmax (wCOV, LN 8.8% vs. bone 12.0%, P < 0.03). On a compartment-based level, wCOVs for volumetric features were ≥22.8%, demonstrating no significant differences between LN and bone lesions (PSMA-TV, P =0.63; TL-PSMA, P =0.9). Findings on an entire tumor burden level were also corroborated in a hottest lesion analysis investigating the SUVmax of the most intense lesion per patient (R 2, 0.99; wCOV, 11.2%). Conclusion: In this prospective test-retest setting, SUV parameters demonstrated high repeatability, in particular in LNs, while volumetric parameters demonstrated low repeatability. Further, the large number of lesions and wide distribution of SUVs included in this analysis allowed for the demonstration of a dependence of repeatability on SUV, with higher SUVs having more robust repeatability.
Subject(s)
Positron Emission Tomography Computed Tomography , Prostatic Neoplasms , Humans , Male , Positron Emission Tomography Computed Tomography/methods , Prospective Studies , Prostatic Neoplasms/diagnostic imaging , Tumor BurdenABSTRACT
BACKGROUND: An updated systematic review and meta-analysis of relevant studies to evaluate the effectiveness of prostate-specific membrane antigen (PSMA)-targeted endoradiotherapy/radioligand therapy (PRLT) in castration resistant prostate cancer (CRPC). METHODS: A systematic search was performed in July 2020 using PubMed/Medline database to update our prior systematic review. The search was limited to papers published from 2019 to June 2020. A total of 472 papers were reviewed. The studied parameters included pooled proportion of patients showing any or ≥50% prostate-specific antigen (PSA) decline after PRLT. Survival effects of PRLT were assessed based on pooled hazard ratios (HRs) of the overall survival (OS) according to any PSA as well as ≥50% PSA decline after PRLT. Response to therapy based on ≥50% PSA decrease after PRLT versus controls was evaluated using Mantel-Haenszel random effect meta-analysis. All p values < 0.05 were considered as statistically significant. RESULTS: A total of 45 publications were added to the prior 24 studies. 69 papers with total of 4157 patients were included for meta-analysis. Meta-analysis of the two recent randomized controlled trials showed that patients treated with 177 Lu-PSMA 617 had a significantly higher response to therapy compared to controls based on ≥50% PSA decrease. Meta-analysis of the HRs of OS according to any PSA decline and ≥50% PSA decline showed survival prolongation after PRLT. CONCLUSIONS: PRLT results in higher proportion of patients responding to therapy based on ≥50% PSA decline compared to controls. Any PSA decline and ≥50% PSA decline showed survival prolongation after PRLT. ADVANCES IN KNOWLEDGE: This is the first meta-analysis to aggregate the recent randomized controlled trials of PRLT which shows CRPC patients had a higher response to therapy after PRLT compared to controls.
Subject(s)
Prostatic Neoplasms, Castration-Resistant , Dipeptides/therapeutic use , Heterocyclic Compounds, 1-Ring/therapeutic use , Humans , Lutetium/therapeutic use , Male , Prostate-Specific Antigen , Prostatic Neoplasms, Castration-Resistant/pathology , Treatment OutcomeABSTRACT
PURPOSE: We developed a theranostic radiopharmaceutical that engages two key cell surface proteases, fibroblast activation protein alpha (FAP) and prostate-specific membrane antigen (PSMA), each frequently overexpressed within the tumor microenvironment (TME). The latter is also expressed in most prostate tumor epithelium. To engage a broader spectrum of cancers for imaging and therapy, we conjugated small-molecule FAP and PSMA-targeting moieties using an optimized linker to provide 64Cu-labeled compounds. METHODS: We synthesized FP-L1 and FP-L2 using two linker constructs attaching the FAP and PSMA-binding pharmacophores. We determined in vitro inhibition constants (Ki) for FAP and PSMA. Cell uptake assays and flow cytometry were conducted in human glioma (U87), melanoma (SK-MEL-24), prostate cancer (PSMA + PC3 PIP and PSMA - PC3 flu), and clear cell renal cell carcinoma lines (PSMA + /PSMA - 786-O). Quantitative positron emission tomography/computed tomography (PET/CT) and tissue biodistribution studies were performed using U87, SK-MEL-24, PSMA + PC3 PIP, and PSMA + 786-O experimental xenograft models and the KPC genetically engineered mouse model of pancreatic cancer. RESULTS: 64Cu-FP-L1 and 64Cu-FP-L2 were produced in high radiochemical yields (> 98%) and molar activities (> 19 MBq/nmol). Ki values were in the nanomolar range for both FAP and PSMA. PET imaging and biodistribution studies revealed high and specific targeting of 64Cu-FP-L1 and 64Cu-FP-L2 for FAP and PSMA. 64Cu-FP-L1 displayed more favorable pharmacokinetics than 64Cu-FP-L2. In the U87 tumor model at 2 h post-injection, tumor uptake of 64Cu-FP-L1 (10.83 ± 1.02%ID/g) was comparable to 64Cu-FAPI-04 (9.53 ± 2.55%ID/g). 64Cu-FP-L1 demonstrated high retention 5.34 ± 0.29%ID/g at 48 h in U87 tumor. Additionally, 64Cu-FP-L1 showed high retention in PSMA + PC3 PIP tumor (12.06 ± 0.78%ID/g at 2 h and 10.51 ± 1.82%ID/g at 24 h). CONCLUSIONS: 64Cu-FP-L1 demonstrated high and specific tumor targeting of FAP and PSMA. This compound should enable imaging of lesions expressing FAP, PSMA, or both on the tumor cell surface or within the TME. FP-L1 can readily be converted into a theranostic for the management of heterogeneous tumors.
Subject(s)
Prostatic Neoplasms , Radiopharmaceuticals , Animals , Male , Mice , Humans , Radiopharmaceuticals/pharmacokinetics , Positron Emission Tomography Computed Tomography/methods , Tissue Distribution , Cell Line, Tumor , Glutamate Carboxypeptidase II/metabolism , Positron-Emission Tomography , Prostatic Neoplasms/pathology , Tumor MicroenvironmentABSTRACT
PURPOSE: Macrophages represent an essential means of sequestration and immune evasion for Mycobacterium tuberculosis. Pulmonary tuberculosis (TB) is characterized by dense collections of tissue-specific and recruited macrophages, both of which abundantly express CSF1R on their outer surface. 4-Cyano-N-(5-(1-(dimethylglycyl)piperidin-4-yl)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-2-yl)-1H-imidazole-2-carboxamide (JNJ-28312141) is a reported high affinity, CSF1R-selective antagonist. We report the radiosynthesis of 4-cyano-N-(5-(1-(N-methyl-N-([11C]methyl)glycyl)piperidin-4-yl)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-2-yl)-1H-imidazole-2-carboxamide ([11C]JNJ-28312141) and non-invasive detection of granulomatous and diffuse lesions in a mouse model of TB using positron emission tomography (PET). METHODS: Nor-methyl-JNJ-28312141 precursor was radiolabeled with [11C]iodomethane to produce [11C]JNJ-28312141. PET/CT imaging was performed in the C3HeB/FeJ murine model of chronic pulmonary TB to co-localize radiotracer uptake with granulomatous lesions observed on CT. Additionally, CSF1R, Iba1 fluorescence immunohistochemistry was performed to co-localize CSF1R target with reactive macrophages in infected and healthy mice. RESULTS: Radiosynthesis of [11C]JNJ-28312141 averaged a non-decay-corrected yield of 18.7 ± 2.1%, radiochemical purity of 99%, and specific activity averaging 658 ± 141 GBq/µmol at the end-of-synthesis. PET/CT imaging in healthy mice showed hepatobiliary [13.39-25.34% ID/g, percentage of injected dose per gram of tissue (ID/g)] and kidney uptake (12.35% ID/g) at 40-50 min post-injection. Infected mice showed focal pulmonary lesion uptake (5.58-12.49% ID/g), hepatobiliary uptake (15.30-40.50% ID/g), cervical node uptake, and renal uptake (11.66-29.33% ID/g). The ratio of infected lesioned lung/healthy lung uptake is 5.91:1, while the ratio of lesion uptake to adjacent infected radiolucent lung is 2.8:1. Pre-administration of 1 mg/kg of unlabeled JNJ-28312141 with [11C]JNJ-28312141 in infected animals resulted in substantial blockade. Fluorescence microscopy of infected and uninfected whole lung sections exclusively co-localized CSF1R staining with abundant Iba1 + macrophages. Healthy lung exhibited no CSF1R staining and very few Iba1 + macrophages. CONCLUSION: [11C]JNJ-28312141 binds specifically to CSF1R + macrophages and delineates granulomatous foci of disease in a murine model of pulmonary TB.
Subject(s)
Positron Emission Tomography Computed Tomography , Tuberculosis , Animals , Biphenyl Compounds , Disease Models, Animal , Imidazoles , Mice , Positron Emission Tomography Computed Tomography/methods , Positron-Emission Tomography/methods , Receptors, Granulocyte-Macrophage Colony-Stimulating Factor , Tomography, X-Ray Computed , Tuberculosis/diagnostic imagingABSTRACT
PURPOSE: Prostate-specific membrane antigen (PSMA) is a promising target for prostate cancer imaging and therapy. The most commonly used scaffold incorporates a glutamate-urea (Glu-Urea) function. We recently developed oxalyldiaminopropionic acid-urea (ODAP-Urea) PSMA ligands in an attempt to improve upon the pharmacokinetic properties of existing agents. Here, we report the synthesis of an optimized 68Ga-labeled ODAP-Urea-based ligand, [68Ga]Ga-P137, and first-in-human results. METHODS: Twelve ODAP-Urea-based ligands were synthesized and radiolabeled with 68Ga in high radiochemical yield and purity. Their PSMA inhibitory capacities were determined using the NAALADase assay. Radioligands were evaluated in mice-bearing 22Rv1 prostate tumors by microPET. Lead compound [68Ga]Ga-P137 was evaluated for stability, cell uptake, and biodistribution. PET imaging of [68Ga]Ga-P137 was performed in three patients head-to-head compared to [68Ga]Ga-PSMA-617. RESULTS: Ligands were synthesized in 11.1-44.4% yield and > 95% purity. They have high affinity to PSMA (Ki of 0.13 to 5.47 nM). [68Ga]Ga-P137 was stable and hydrophilic. [68Ga]Ga-P137 showed higher uptake than [68Ga]Ga-PSMA-617 in tumor-bearing mice at 6.43 ± 0.98%IA/g vs 3.41 ± 1.31%IA/g at 60-min post-injection. In human studies, the normal organ biodistribution of [68Ga]Ga-P137 was grossly equivalent to that of [68Ga]Ga-PSMA-617 except for within the urinary tract, in which [68Ga]Ga-P137 demonstrated lower uptake. CONCLUSION: The optimized ODAP-Urea-based ligand [68Ga]Ga-P137 can image PSMA in xenograft models and humans, with lower bladder accumulation to the Glu-Urea-based agent, [68Ga]Ga-PSMA-617, in a preliminary, first-in-human study. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04560725, Registered 23 September 2020. https://clinicaltrials.gov/ct2/show/NCT04560725.
Subject(s)
Glutamate Carboxypeptidase II , Prostatic Neoplasms , Amino Acids, Diamino , Animals , Antigens, Surface/metabolism , Cell Line, Tumor , Gallium Radioisotopes , Glutamate Carboxypeptidase II/metabolism , Humans , Male , Mice , Positron-Emission Tomography/methods , Prostatic Neoplasms/diagnostic imaging , Prostatic Neoplasms/pathology , Tissue Distribution , UreaABSTRACT
Involvement of oxidative stress in the pathophysiology of schizophrenia (SZ) is suggested by studies of peripheral tissue. Nonetheless, it is unclear how such biological changes are linked to relevant, pathological neurochemistry, and brain function. We designed a multi-faceted study by combining biochemistry, neuroimaging, and neuropsychology to test how peripheral changes in a key marker for oxidative stress, glutathione (GSH), may associate with central neurochemicals or neuropsychological performance in health and in SZ. GSH in dorsal anterior cingulate cortex (dACC) was acquired as a secondary 3T 1H-MRS outcome using a MEGA-PRESS sequence. Fifty healthy controls and 46 patients with SZ were studied cross-sectionally, and analyses were adjusted for effects of confounding variables. We observed lower peripheral total GSH in SZ compared to controls in extracellular (plasma) and intracellular (lymphoblast) pools. Total GSH levels in plasma positively correlated with composite neuropsychological performance across the total population and within patients. Total plasma GSH levels were also positively correlated with the levels of Glx in the dACC across the total population, as well as within each individual group (controls, patients). Furthermore, the levels of dACC Glx and dACC GSH positively correlated with composite neuropsychological performance in the patient group. Exploring the relationship between systemic oxidative stress (in particular GSH), central glutamate, and cognition in SZ will benefit further from assessment of patients with more varied neuropsychological performance.
Subject(s)
Schizophrenia , Brain/diagnostic imaging , Cognition , Glutamic Acid , Glutathione , Gyrus Cinguli , HumansABSTRACT
The introduction of immunotherapy with immune-checkpoint inhibitors (ICIs) has revolutionized cancer treatment paradigms. Since FDA approval of the first ICI in 2011, multiple additional ICIs have been approved and granted marketing authorization, and many promising agents are in early clinical adoption. Due to the distinctive biologic mechanisms of ICIs, the patterns of tumor response and progression seen with immunotherapy differ from those observed with cytotoxic chemothera-pies. With increasing clinical adoption of immunotherapy, it is critical for radiologists to recognize different response patterns and common pitfalls to avoid misinterpretation of imaging studies or prompt premature cessation of potentially effective treatment. This review provides an overview of ICIs and their mechanisms of action and discusses anatomic and metabolic immune-related response assessment methods, typical and atypical patterns of immunotherapy response (including pseudoprogression, hyperprogression, dissociated response, and durable response), and common imaging features of immune-related adverse events. Future multicenter trials are needed to validate the proposed immune-related response criteria and identify the functional imaging markers of early treatment response and survival.
Subject(s)
Immunotherapy , Neoplasms , Humans , Immune Checkpoint Inhibitors , Immunotherapy/adverse effects , Inflammation , Neoplasms/diagnostic imaging , Neoplasms/drug therapy , Response Evaluation Criteria in Solid TumorsABSTRACT
While neuroinflammation is an evolving concept and the cells involved and their functions are being defined, microglia are understood to be a key cellular mediator of brain injury and repair. The ability to measure microglial activity specifically and noninvasively would be a boon to the study of neuroinflammation, which is involved in a wide variety of neuropsychiatric disorders including traumatic brain injury, demyelinating disease, Alzheimer's disease (AD), and Parkinson's disease, among others. We have developed [11C]CPPC [5-cyano-N-(4-(4-[11C]methylpiperazin-1-yl)-2-(piperidin-1-yl)phenyl)furan-2-carboxamide], a positron-emitting, high-affinity ligand that is specific for the macrophage colony-stimulating factor 1 receptor (CSF1R), the expression of which is essentially restricted to microglia within brain. [11C]CPPC demonstrates high and specific brain uptake in a murine and nonhuman primate lipopolysaccharide model of neuroinflammation. It also shows specific and elevated uptake in a murine model of AD, experimental allergic encephalomyelitis murine model of demyelination and in postmortem brain tissue of patients with AD. Radiation dosimetry in mice indicated [11C]CPPC to be safe for future human studies. [11C]CPPC can be synthesized in sufficient radiochemical yield, purity, and specific radioactivity and possesses binding specificity in relevant models that indicate potential for human PET imaging of CSF1R and the microglial component of neuroinflammation.
Subject(s)
Macrophage Colony-Stimulating Factor/metabolism , Microglia/metabolism , Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/metabolism , Alzheimer Disease/metabolism , Animals , Brain/metabolism , Disease Models, Animal , Inflammation/metabolism , Male , Mice , Mice, Inbred C57BL , Plaque, Amyloid/metabolism , Positron-Emission Tomography/methods , Primates , Radiopharmaceuticals/metabolismABSTRACT
Limited tumor nanoparticle accumulation remains one of the main challenges in cancer nanomedicine. Here, we demonstrate that subtherapeutic photodynamic priming (PDP) enhances the accumulation of nanoparticles in subcutaneous murine prostate tumors â¼3-5-times without inducing cell death, vascular destruction, or tumor growth delay. We also found that PDP resulted in an â¼2-times decrease in tumor collagen content as well as a significant reduction of extracellular matrix density in the subendothelial zone. Enhanced nanoparticle accumulation combined with the reduced extravascular barriers improved therapeutic efficacy in the absence of off-target toxicity, wherein 5 mg/kg of Doxil with PDP was equally effective in delaying tumor growth as 15 mg/kg of Doxil. Overall, this study demonstrates the potential of PDP to enhance tumor nanomedicine accumulation and alleviate tumor desmoplasia without causing cell death or vascular destruction, highlighting the utility of PDP as a minimally invasive priming strategy that can improve therapeutic outcomes in desmoplastic tumors.