psma-617 and Prostatic-Neoplasms

Radioligand therapy (RLT) directed against prostate-specific membrane antigen (PSMA) enables tumor-specific treatment directed against PSMA-overexpressing prostate cancer cells. Several PSMA ligands such as PSMA-617 or PSMA-I&T have been developed that can be labeled with β‑radiating lutetium-177. These are currently applied in compassionate use programs to treat metastatic castration-resistant prostate cancer (mCRPC). PSMA-directed RLT is currently being offered in several nuclear medicine departments throughout Germany. Several retrospective case series demonstrate its activity with a prostate-specific antigen (PSA) decrease >50% in 30-60% of mCRPC patients. The toxicity seems to be low. Hematologic grade 4 toxicity has not been observed and grade 3 toxicities rarely occur. The main nonhematologic adverse events are intermittent dry mouth because of unspecific PSMA expression in the salivary glands as well as fatigue and nausea. Currently there are no prospective studies available for evaluation of PSMA-targeted RLT and a survival benefit over approved standard therapies such as abiraterone, enzalutamide, radium-223-dichloride, docetaxel or cabazitaxel has not been shown. PSMA-targeted RLT should therefore currently only be offered after critical evaluation in patients who exhausted the approved standard therapies.

Topics: Antigens, Surface; Dipeptides; Evidence-Based Medicine; Glutamate Carboxypeptidase II; Heterocyclic Compounds, 1-Ring; Humans; Isotope Labeling; Lutetium; Male; Molecular Targeted Therapy; Prostate-Specific Antigen; Prostatic Neoplasms; Radiopharmaceuticals; Radiotherapy; Treatment Outcome

For prostate-specific membrane antigen-directed radioligand therapy (PSMA-RLT), [ 177 Lu]Lu-PSMA-617 and [ 177 Lu]Lu-PSMA-I&T are the currently preferred compounds. Recent preclinical studies suggested ~30x higher kidney absorbed dose for [ 177 Lu]Lu-PSMA-I&T compared to [ 177 Lu]Lu-PSMA-617, which may lead to an increased risk of kidney toxicity. We performed two single-centre, prospective dosimetry studies with either [ 177 Lu]Lu-PSMA-617 or [ 177 Lu]Lu-PSMA-I&T, using an identical dosimetry protocol. We evaluated the absorbed doses of both 177 Lu-labelled radioligands in human kidneys.. 3D SPECT/computed tomography (CT) imaging of the kidneys was performed after PSMA-RLT in cancer patients with PSMA-positive disease and an adequate glomerular filtration rate (≥50 mL/min). Ten metastatic hormone-sensitive prostate cancer patients (mHSPC) were treated with [ 177 Lu]Lu-PSMA-617 and 10 advanced salivary gland cancer (SGC) patients were treated with [ 177 Lu]Lu-PSMA-I&T. SPECT/CT imaging was performed at five timepoints (1 h, 24 h, 48 h, 72 h, and 168 h post-injection). In mHSPC patients, SPECT/CT imaging was performed after cycles 1 and 2 (cumulative activity: 9 GBq) and in SGC patients only after cycle 1 (activity: 7.4 GBq). Kidney absorbed dose was calculated using organ-based dosimetry.. The median kidney absorbed dose was 0.49 Gy/GBq (range: 0.34-0.66) and 0.73 Gy/GBq (range: 0.42-1.31) for [ 177 Lu]Lu-PSMA-617 and [ 177 Lu]Lu-PSMA-I&T, respectively (independent samples t test; P  = 0.010).. This study shows that the kidney absorbed dose for [ 177 Lu]Lu-PSMA-617 and [ 177 Lu]Lu-PSMA-I&T differs, with a ~1.5x higher median kidney absorbed dose for [ 177 Lu]Lu-PSMA-I&T. This difference in the clinical setting is considerably smaller than observed in preclinical studies and may not hamper treatments with [ 177 Lu]Lu-PSMA-I&T.

Topics: Humans; Kidney; Male; Prospective Studies; Prostatic Neoplasms; Radiation Dosage

We aimed to compare the diagnostic performance of 68 Ga-P16-093 and 68 Ga-PSMA-617 PET/CT in primary prostate cancer (PCa) patients.. Thirty untreated primary PCa patients were enrolled. Each patient underwent 68 Ga-P16-093 and 68 Ga-PSMA-617 PET/CT within a week. In addition to visual analysis, SUV was measured for semiquantitative comparison and correlation analysis.. 68 Ga-P16-093 PET/CT detected more positive tumors than 68 Ga-PSMA-617 PET/CT (67 vs 56, P = 0.002), especially for intraprostatic lesions (29 vs 24, P = 0.025) and lymph node metastases (23 vs 17, P = 0.034). Further, 68 Ga-P16-093 PET/CT exhibited significantly higher SUV max of matched tumors (18.3 ± 14.4 vs 13.9 ± 11.8, P < 0.001). Besides, the SUV max of high-risk patients (based on D'Amico classification) on 68 Ga-P16-093 PET/CT was significantly higher than that of low- and intermediate-risk PCa patients (20.9 ± 9.9 vs 8.9 ± 9.1 vs 10.1 ± 5.2, P = 0.007). The SUV max of tumor measured by 68 Ga-P16-093 PET/CT had a moderate association with biopsy Gleason score ( r = 0.462, P = 0.005) and prostate-specific antigen value ( r = 0.491, P = 0.002), and significantly correlated with PSMA expression ( r = 0.732, P < 0.001).. 68 Ga-P16-093 PET/CT exhibited higher tumor uptake and potentially better tumor detection capability than 68 Ga-PSMA-617 PET/CT, which suggested that 68 Ga-P16-093 may be more suitable in the diagnosis and staging of primary PCa patients.

Topics: Edetic Acid; Gallium Isotopes; Gallium Radioisotopes; Humans; Male; Oligopeptides; Pilot Projects; Positron Emission Tomography Computed Tomography; Prostate-Specific Antigen; Prostatic Neoplasms

The aim of this study was to systematically evaluate the effect of thresholding algorithms used in computer vision for the quantification of prostate-specific membrane antigen positron emission tomography (PET) derived tumor volume (PSMA-TV) in patients with advanced prostate cancer. The results were validated with respect to the prognostication of overall survival in patients with advanced-stage prostate cancer.. A total of 78 patients who underwent [. The whole-body PSMA-TVs, quantified using different thresholding methods, demonstrate a high positive correlation with the baseline methods. We observed the highest correlation with generalized histogram thresholding (GHT) (Pearson r (r), p value (p): r = 0.977, p < 0.001) and Sauvola thresholding (r = 0.974, p < 0.001) and the lowest correlation with Multiotsu (r = 0.877, p < 0.001) and Yen thresholding methods (r = 0.878, p < 0.001). The median survival time of all patients was 9.87 months (95% CI [9.3 to 10.13]). Stratification by median whole-body PSMA-TV resulted in a median survival time from 11.8 to 13.5 months for the patient group with lower tumor burden and 6.5 to 6.6 months for the patient group with higher tumor burden. The patient group with lower tumor burden had significantly higher probability of survival (p < 0.00625) in eight out of nine thresholding methods (Fig. 2); those methods were SUVmax50 (p = 0.0038), SUV ≥3 (p = 0.0034), Multiotsu (p = 0.0015), Yen (p = 0.0015), Niblack (p = 0.001), Sauvola (p = 0.0001), Otsu (p = 0.0053), and Li thresholding (p = 0.0053).. Thresholding methods commonly used in computer vision are promising tools for the semiautomatic quantification of whole-body PSMA-TV in [

Topics: Gallium Radioisotopes; Humans; Male; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Prostate-Specific Antigen; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Tumor Burden

Topics: Dipeptides; Humans; Male; Prostate-Specific Antigen; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant

For the implementation of suitable radiation safety measures in [. Both the short-term (up to 24 h, n = 28 cycles) and long-term kinetics (up to 7 weeks, n = 35 samples) were evaluated by collection of urine samples. Samples were measured on a scintillation counter to determine excretion kinetics.. The mean excretion half-time during the first 20 h was 4.9 h. Kinetics was significantly different for patients with kidney function below or above eGFR 65 ml/min. Calculated skin equivalent dose in case of urinary contamination was between 50 and 145 mSv when it was caused between 0 and 8 h p.i.. Measurable amounts of. Excretion kinetics of [

Topics: Dipeptides; Heterocyclic Compounds, 1-Ring; Humans; Lutetium; Male; Prostate-Specific Antigen; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Radiopharmaceuticals

Topics: Carcinoma; Castration; Humans; Male; Prostate; Prostatic Neoplasms

Prostate-specific membrane antigen (PSMA), highly expressed in prostate cancer, is a promising target for radionuclide therapy. Auger electron-emitting radionuclides are well suited for targeted radionuclide therapy if they can be delivered close to the DNA of the targeted cells. This preclinical study evaluated the theranostic pair [

Topics: Animals; Antigens, Surface; Cell Line, Tumor; Electrons; Glutamate Carboxypeptidase II; Humans; Male; Mice; Prostatic Neoplasms; Radioisotopes; Radiopharmaceuticals; Tissue Distribution

The aim of this prospective clinical study was to evaluate the potential of the prostate specific membrane antigen (PSMA) targeting ligand, [

Topics: Adult; Brain Neoplasms; Chronic Disease; Contrast Media; Gallium Radioisotopes; Glioblastoma; Humans; Magnetic Resonance Imaging; Male; Positron-Emission Tomography; Prospective Studies; Prostatic Neoplasms

Topics: Animals; Cell Line, Tumor; Dipeptides; Heterocyclic Compounds, 1-Ring; Humans; Lutetium; Male; Mice; Mice, SCID; Prostate-Specific Antigen; Prostatic Neoplasms; Radioisotopes; Radiopharmaceuticals; Tissue Distribution; Xenograft Model Antitumor Assays

In the last decade, the development of new radiopharmaceuticals for the imaging and therapy of prostate cancer has been a highly active and important area of research, especially focusing on the prostate-specific membrane antigen (PSMA), an antigen which is upregulated in prostate, as well as in other tumor cells. A large variety of PSMA ligands have been radiolabeled, to date. Among the various derivatives, PSMA-617 resulted to be one of the most interesting in terms of interaction with the antigen and clinical properties, and its lutetium-177 labeled version has recently been approved by regulatory agencies for therapeutic purposes. For this reasons, the radiolabeling with fluorine-18 of a PSMA-617 derivative might be of interest. Beside other methodologies to radiolabel macromolecules with fluorine-18, the "click-chemistry" approach resulted to be very useful, and the copper-catalyzed azide-alkyne cycloaddition (CuAAC) is considered one of most efficient and reliable. This paper proposes the synthesis of a suitable precursor for the radiolabeling with fluorine-18 of a new PSMA-617 derivative. The whole radiosynthetic procedure has been fully automated, and the final product, which proved to be stable in plasma, has been obtained with radiochemical yield and purity suitable for subsequent preclinical studies.

Topics: Cell Line, Tumor; Dipeptides; Fluorine Radioisotopes; Heterocyclic Compounds, 1-Ring; Humans; Male; Prostate-Specific Antigen; Prostatic Neoplasms; Radiopharmaceuticals

For localization of biochemical recurrence of prostate cancer, 68Ga-PSMA-11 PET/CT imaging was performed in a 66-year-old man with no suspicious findings at 1 hour p.i. Additional 89Zr-PSMA-617 PET/CT revealed a small local recurrence in the prostate bed, facilitating consecutive local therapy. This interesting image points to the potential of PET/CT with 89Zr-labeled PSMA ligands, for example, 89Zr-PSMA-617, for identifying the source of biochemical recurrence despite otherwise negative imaging including conventional PSMA PET/CT.

Topics: Aged; Dipeptides; Edetic Acid; Gallium Isotopes; Gallium Radioisotopes; Heterocyclic Compounds, 1-Ring; Humans; Male; Neoplasm Recurrence, Local; Positron Emission Tomography Computed Tomography; Prostate-Specific Antigen; Prostatic Neoplasms; Radioisotopes; Zirconium

Hepatocellular carcinoma (HCC) is a malignant tumor associated with high morbidity and mortality rates. In many non-prostate solid tumors such as HCC, prostate-specific membrane antigens (PSMA) are overexpressed in tumor-associated endothelial cells. Therefore, the aim of this study was to evaluate the performance of [. [. Low PSMA expression level of HepG2 and HuH-7 cells was observed, and the cellular uptake and blocking study confirmed the non-specificity of the PSMA-targeted probe binding to HepG2 and HuH-7 cells. In the subcutaneous xenograft models, the tumor uptakes at 0.5 h were 0.76 ± 0.12%ID/g (HepG2 tumors) and 0.78 ± 0.08%ID/g (HuH-7 tumors), respectively, which were significantly higher than those of the blocking groups (0.23 ± 0.04%ID/g and 0.20 ± 0.04%ID/g, respectively). In the orthotopic xenograft models, PET images clearly displayed the tumor locations based on the preferential accumulation of [. In this study, in vivo PET on different types of HCC xenograft models illustrated high uptake within tumors, which confirmed that [

Topics: Animals; Carcinoma, Hepatocellular; Cell Line, Tumor; Dipeptides; Endothelial Cells; Endothelium; Gallium Radioisotopes; Glutamate Carboxypeptidase II; Heterocyclic Compounds, 1-Ring; Humans; Liver Neoplasms; Male; Positron-Emission Tomography; Prostate-Specific Antigen; Prostatic Neoplasms; Tissue Distribution

While [. We successfully performed small lesion dosimetry and showed that the tumor sink effect in mHSPC patients is of less concern than was expected. Tumor-to-organ ratio of absorbed dose was high and tumor uptake correlates with PSA response. Additional treatment cycles are legitimate in terms of organ toxicity and could lead to better tumor response.

Topics: Hormones; Humans; Lutetium; Male; Organs at Risk; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms; Radiation Dosage; Radiopharmaceuticals; Single Photon Emission Computed Tomography Computed Tomography; Treatment Outcome

Lu-177-based, targeted radiotherapeutics/endoradiotherapies are an emerging clinical tool for the management of various cancers. The chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) remains the workhorse for such applications but can limit apparent molar activity or efficient charge modulation, which can impact target binding and, as a consequence, target efficacy. Previously, our lab had developed the small, rare earth selective bifunctional chelator, picaga, as an efficient bifunctional chelator for scandium and lutetium isotopes. Here, we assess the performance of these constructs for therapy in prostate-specific membrane antigen (PSMA)-expressing tumor xenografts. To assess the viability of picaga conjugates in conjunction with long in vivo circulation, a picaga conjugate functionalized with a serum albumin binding moiety,

Topics: Animals; Chelating Agents; Dipeptides; Heterocyclic Compounds, 1-Ring; Humans; Lutetium; Male; Mice; Prostate-Specific Antigen; Prostatic Neoplasms; Radioisotopes; Radiopharmaceuticals; Scandium; Tissue Distribution

Topics: Dipeptides; Heterocyclic Compounds, 1-Ring; Humans; Lutetium; Male; Prostate-Specific Antigen; Prostatic Neoplasms; Radioisotopes

Topics: Dipeptides; Heterocyclic Compounds, 1-Ring; Humans; Lutetium; Male; Prostate-Specific Antigen; Prostatic Neoplasms; Radioisotopes

Topics: Dipeptides; Heterocyclic Compounds, 1-Ring; Humans; Lutetium; Male; Prostate-Specific Antigen; Prostatic Neoplasms; Radioisotopes

Topics: Dipeptides; Heterocyclic Compounds, 1-Ring; Humans; Lutetium; Male; Prostate-Specific Antigen; Prostatic Neoplasms; Radioisotopes

Topics: Adenocarcinoma; Antibodies, Bispecific; Antibodies, Neoplasm; Antigens, Surface; Biomarkers, Tumor; Clinical Trials as Topic; Dipeptides; Docetaxel; Glutamate Carboxypeptidase II; Heterocyclic Compounds, 1-Ring; Humans; Immunoconjugates; Immunotherapy, Adoptive; Lutetium; Male; Molecular Targeted Therapy; Nanoparticles; Neoplasm Proteins; Prostate-Specific Antigen; Prostatic Neoplasms; Radioisotopes; Randomized Controlled Trials as Topic

Topics: Dipeptides; Follow-Up Studies; Heterocyclic Compounds, 1-Ring; Humans; Lutetium; Male; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms; Radioisotopes; Theranostic Nanomedicine

Prostate-specific membrane antigen (PSMA)-based imaging and therapy are increasingly used in the management of prostate cancer. However, low PSMA surface expression in certain patients is a limitation for PSMA-based technologies. We have previously shown that high doses of dutasteride, a 5α-reductase inhibitor generally used for the treatment of benign prostatic enlargement, increase the PSMA expression in vitro. We now further analyzed the concentration- and time-dependent effects of dutasteride in LNCaP cells.. Androgen receptor (AR) expressing prostate cancer cells (LNCaP) were treated for 7 to 14 days with vehicle control (0.1% dimethyl sulfoxide) or different concentrations of dutasteride (0.25 , 0.5 , 1 , and 5  μM). In addition to cell proliferation, PSMA surface expression was assessed using flow cytometry (FACS) and immunocytochemistry. Total PSMA and AR expression was analyzed by capillary western immunoassay (WES). In addition, tumor cell uptake and internalization assays of. Dutasteride treatment resulted in a significant upregulation of PSMA surface expression compared to vehicle control after 7 days in all tested concentrations. After 14 days a further, concentration-dependent increase of PSMA surface expression was detectable. Total PSMA protein expression significantly increased after treatment of cells with high concentrations of dutasteride using 5  μM for 7 or 14 days. However, when lower concentrations were used total PSMA expression was not significantly altered compared to vehicle control. Further testing revealed a dose-dependent increase in uptake and internalization of. Our investigations revealed a concentration- and time-dependent effect of dutasteride on PSMA expression and uptake of

Topics: 5-alpha Reductase Inhibitors; Antigens, Surface; Cell Line, Tumor; Dipeptides; Dose-Response Relationship, Drug; Dutasteride; Glutamate Carboxypeptidase II; Heterocyclic Compounds, 1-Ring; Humans; Lutetium; Male; Prostate; Prostate-Specific Antigen; Prostatic Neoplasms; Radioisotopes; Receptors, Androgen; Up-Regulation

Ga-labeled prostate-specific membrane antigen inhibitors and Ga-labeled gastrin-releasing peptide receptor antagonists showed interesting results for staging biochemically recurrent prostate cancer. In this case, Ga-prostate-specific membrane antigen-617 PET/CT, Ga-RM2 PET/CT, and F-choline PET/CT were performed in a patient (66-year-old man, prostate-specific antigen = 6.7 ng/mL) with biopsy-proven Gleason 9 (5 + 4) prostate cancer, candidate for radical prostatectomy and lymph node dissection.

Topics: Aged; Choline; Dipeptides; Gallium Radioisotopes; Heterocyclic Compounds, 1-Ring; Humans; Male; Neoplasm Staging; Oligopeptides; Positron Emission Tomography Computed Tomography; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Risk

Here we report the 18F labeling of a prostate specific membrane antigen (PSMA) ligand via a strain promoted oxa-dibenzocyclooctyne (ODIBO)- or bicyclo[6.1.0]nonyne (BCN)-azide reaction. Although ODIBO reacts with azide 20 fold faster than BCN, in vivo PET imaging suggests that 18F-BCN-azide-PSMA demonstrated much higher tumor uptake and a much higher tumor to background contrast.

Topics: Alkynes; Animals; Antigens, Surface; Azides; Bridged Bicyclo Compounds; Cyclooctanes; Dipeptides; Fluorine Radioisotopes; Glutamate Carboxypeptidase II; Heterocyclic Compounds, 1-Ring; Humans; Hydrocarbons, Fluorinated; Hydrophobic and Hydrophilic Interactions; Kinetics; Ligands; Male; Mice; Positron-Emission Tomography; Prostate-Specific Antigen; Prostatic Neoplasms; Protein Binding; Radiopharmaceuticals; Xenograft Model Antitumor Assays

Intraoperative identification of lymph node (LN) metastases (LNM) detected on preoperative PSMA PET/CT may be facilitated by PSMA radioguided surgery with the use of a gamma probe. We evaluated the uptake of. Six patients with prostate cancer (PCa) with suspicion of LNM on preoperative PSMA PET/CT underwent. Overall 310 LN (mean 52 ± 19.7) were removed from 74 subregions (mean 12 ± 3.7). Of the 310 LN, 35 turned out to be LNM on histopathology. Separation of the samples from all subregions resulted in 318 single specimens: 182 PCa-negative LN samples with 275 LN, 35 single LNM samples, 3 non-nodal PCa tissue samples and 98 fibrofatty tissue samples. The median SULs of nonaffected LN (0.16) and affected LN (13.2) were significantly different (p < 0.0001). Based on 38 tumour-containing and 182 tumour-free specimens, ROC analysis revealed an area under the curve of 0.976 (95% CI 0.95-1.00, p < 0.0001). Using a SUL cut-off value of 1.136, sensitivity, specificity, positive predictive value, negative predictive value and accuracy in discriminating affected from nonaffected LN were 92.1% (35/38), 98.9% (180/182), 94.6% (35/37), 98.4% (180/183) and 97.7% (215/220), respectively.. Ex situ analysis at the level of single LN showed that

Topics: Aged; Biological Transport; Dipeptides; Heterocyclic Compounds, 1-Ring; Humans; Indium Radioisotopes; Isotope Labeling; Lymph Node Excision; Lymphatic Metastasis; Male; Positron Emission Tomography Computed Tomography; Prostate-Specific Antigen; Prostatic Neoplasms; Radioactive Tracers

Prostate cancer is the most frequently diagnosed malignant tumor in men worldwide. Prostate-specific membrane antigen (PSMA) is a surface molecule specifically expressed by prostate tumors that has been shown to be a valid target for internal radionuclide therapy in both preclinical and clinical settings. The most common radiotherapeutic agent is the small molecule

Topics: Animals; Dipeptides; Evans Blue; Heterocyclic Compounds, 1-Ring; Humans; Lutetium; Male; Mice; Positron-Emission Tomography; Prostate-Specific Antigen; Prostatic Neoplasms; Radiopharmaceuticals; Xenograft Model Antitumor Assays; Yttrium Radioisotopes

[. Fifty-five patients with castrate-resistant metastatic prostate cancer treated with at least three cycles of [. None of the 55 patients experienced severe nephrotoxicity (grade 3/4). In 14 patients (25%), we observed increased creatinine levels of CTC 1° or 2°. There were 16 cases of increased GFR (grade 1/2). At the baseline, only 14 patients had elevated cystatin C. However, post-therapeutic cystatin C was elevated in 32 patients (58%). A significant effect on renal function was found for age (p = 0.049), hypertension (p = 0.001) and pre-existing kidney disease (p = 0.001). The most reliable predictive markers of nephrotoxicity were TER-MAG3 and cystatin C.. Renal toxicity in patients treated with [

Topics: Aged; Dipeptides; Heterocyclic Compounds, 1-Ring; Hormones; Humans; Kidney; Ligands; Lutetium; Male; Neoplasm Metastasis; Prostate-Specific Antigen; Prostatic Neoplasms; Radioisotopes; Risk Factors; Time Factors; Treatment Failure

In recent years, several radiotracers targeting the prostate-specific membrane antigen (PSMA) have been introduced. Some of them have had a high clinical impact on the treatment of patients with prostate cancer. However, the number of

Topics: Animals; Antigens, Surface; Cell Line, Tumor; Dipeptides; Fluorine Radioisotopes; Glutamate Carboxypeptidase II; Heterocyclic Compounds, 1-Ring; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Positron-Emission Tomography; Prostate-Specific Antigen; Prostatic Neoplasms; Radiopharmaceuticals; Reproducibility of Results; Sensitivity and Specificity

PSMA-617 is reported to exhibit very high binding affinity towards PSMA receptors, over-expressed on prostate cancer cells and therefore, (177)Lu-labeled PSMA-617 is expected to play a pivotal role in the clinical management of patients suffering from ca prostate. The objective of the present study is to formulate the patient dose of (177)Lu-labeled PSMA-617, pre-clinical studies in animal model and clinical investigation in limited number of prostate cancer patients as well evaluating its potential for theranostic application.. Patient dose of 7.4 GBq (200 mCi) of (177)Lu-labeled PSMA-617 was prepared by incubating 100 μg of PSMA-617 with (177)LuCl3 at 95 °C for 15 minutes. Radiochemical purity as well as in-vitro stability of the preparation was determined by PC and HPLC methods. The pharmacokinetic behavior and in-vivo distribution of the agent were studied by carrying out biodistribution studies in normal male Wistar rats. Preliminary clinical investigation was performed in 7 patients suffering from prostate cancer.. The complex was prepared with >98% radiochemical purity under the optimized reaction protocols and the preparation exhibited adequate in-vitro stability. Biodistribution studies revealed no significant uptake in any of the major organ/tissue along with major clearance through renal pathway. Clinical studies showed similar distribution in lesions and physiologic areas of uptake as seen in diagnostic (68)Ga-PSMA-11 PET scans performed earlier.. Preliminary clinical studies indicated the promising potential of the agent for theranostic applications. However, further investigations in large pool of patients are warranted to establish the theranostic potential of the agent.

Topics: Animals; Cell Line, Tumor; Dipeptides; Drug Stability; Heterocyclic Compounds, 1-Ring; Humans; Lutetium; Male; Positron-Emission Tomography; Prostate-Specific Antigen; Prostatic Neoplasms; Radiation Dosage; Rats; Rats, Wistar; Tissue Distribution; Translational Research, Biomedical

Targeted radionuclide therapy using (177) Lu-labeled peptidomimetic inhibitor of prostate specific membrane antigen (PSMA) viz. PSMA-617 is emerging as one the most effective strategies for management of metastatic prostate cancer, which is one of the leading causes of cancer related death. The aim of the present study is to develop a robust and easily adaptable protocol for formulation of therapeutic dose of (177) Lu-PSMA-617 at hospital radiopharmacy using moderate specific activity (177) Lu available at an affordable cost. Extensive radiochemical studies were performed to optimize the required [PSMA-617] / [Lu] ratio and other parameters to formulate 7.4 GBq dose of (177) Lu-PSMA-617. Based on these, 7.4 GBq therapeutic dose of (177) Lu-PSMA-617 was formulated by incubating 160 µg of PSMA-617 with indigenously produced (177) LuCl3 (555 GBq/µg specific activity of (177) Lu) at 90 °C for 30 min. The radiochemical purity of the formulation was 98.3 ± 0.6% (n = 7) which was retained to the extent of >95% after 7 d in normal saline at room temperature and >96% after 2 d in human serum at 37 °C. Preliminary clinical studies showed specific targeting of the agent in the lesion sites and similar physiological distribution as in diagnostic (68) Ga-PSMA-11 PET scans performed earlier. The developed optimized protocol for formulating therapeutic dose of (177) Lu-PSMA-617 could be useful for large number of nuclear medicine therapy clinics across the world having access to moderate specific activity (177) Lu at an affordable cost.

Topics: Aged; Antigens, Surface; Dipeptides; Drug Stability; Glutamate Carboxypeptidase II; Heterocyclic Compounds, 1-Ring; Humans; Lutetium; Male; Middle Aged; Positron-Emission Tomography; Prostate-Specific Antigen; Prostatic Neoplasms; Quality Control; Radiochemistry; Radioisotopes

Despite many advances in the past years, the treatment of metastatic prostate cancer still remains challenging. In recent years, prostate-specific membrane antigen (PSMA) inhibitors were intensively studied to develop low-molecular-weight ligands for imaging prostate cancer lesions by PET or SPECT. However, the endoradiotherapeutic use of these compounds requires optimization with regard to the radionuclide-chelating agent and the linker moiety between chelator and pharmacophore, which influence the overall pharmacokinetic properties of the resulting radioligand. In an effort to realize both detection and optimal treatment of prostate cancer, a tailor-made novel naphthyl-containing DOTA-conjugated PSMA inhibitor has been developed.. The peptidomimetic structure was synthesized by solid-phase peptide chemistry and characterized using reversed-phase high-performance liquid chromatography and matrix-assisted laser desorption/ionization mass spectrometry. Subsequent (67/68)Ga and (177)Lu labeling resulted in radiochemical yields of greater than 97% or greater than 99%, respectively. Competitive binding and internalization experiments were performed using the PSMA-positive LNCaP cell line. The in vivo biodistribution and dynamic small-animal PET imaging studies were investigated in BALB/c nu/nu mice bearing LNCaP xenografts.. The chemically modified PSMA inhibitor PSMA-617 demonstrated high radiolytic stability for at least 72 h. A high inhibition potency (equilibrium dissociation constant [K(i)] = 2.34 ± 2.94 nM on LNCaP; K(i) = 0.37 ± 0.21 nM enzymatically determined) and highly efficient internalization into LNCaP cells were demonstrated. The small-animal PET measurements showed high tumor-to-background contrasts as early as 1 h after injection. Organ distribution revealed specific uptake in LNCaP tumors and in the kidneys 1 h after injection. With regard to therapeutic use, the compound exhibited a rapid clearance from the kidneys from 113.3 ± 24.4 at 1 h to 2.13 ± 1.36 percentage injected dose per gram at 24 h. The favorable pharmacokinetics of the molecule led to tumor-to-background ratios of 1,058 (tumor to blood) and 529 (tumor to muscle), respectively, 24 h after injection.. The tailor-made DOTA-conjugated PSMA inhibitor PSMA-617 presented here is sustainably refined and advanced with respect to its tumor-targeting and pharmacokinetic properties by systematic chemical modification of the linker region. Therefore, this radiotracer is suitable for a first-in-human theranostic application and may help to improve the clinical management of prostate cancer in the future.

Topics: Animals; Antigens, Surface; Cell Line, Tumor; Chelating Agents; Chromatography, High Pressure Liquid; Dipeptides; Glutamate Carboxypeptidase II; Heterocyclic Compounds, 1-Ring; Humans; Lutetium; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Peptides; Positron-Emission Tomography; Prostate-Specific Antigen; Prostatic Neoplasms; Radiopharmaceuticals; Radiotherapy; Reproducibility of Results; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Tissue Distribution

Topics: Antigens, Surface; Awards and Prizes; Baltimore; Dipeptides; Gallium; Glutamate Carboxypeptidase II; Heterocyclic Compounds, 1-Ring; History, 21st Century; Humans; Lutetium; Male; Neoplasm Metastasis; Nuclear Medicine; Prostate-Specific Antigen; Prostatic Neoplasms; Radioisotopes; Radionuclide Imaging; Societies, Medical

PET imaging with the prostate-specific membrane antigen (PSMA)-targeted radioligand (68)Ga-PSMA-11 is regarded as a significant step forward in the diagnosis of prostate cancer (PCa). More recently, a PSMA ligand was developed that can be labeled with (68)Ga, (111)In, (177)Lu, and (90)Y. This ligand, named PSMA-617, therefore enables both diagnosis and therapy of PCa. The aims of this evaluation were to clinically investigate the distribution of (68)Ga-PSMA-617 in normal tissues and in PCa lesions as well as to evaluate the radiation exposure by the radioligand in PET imaging.. Nineteen patients, most of them with recurrent PCa, were referred for (68)Ga-PSMA-617 PET/CT. The quantitative assessment of tracer uptake of several organs and of 53 representative tumor lesions was performed in 15 patients at 1 and 3 h after injection. In 4 additional patients, the same procedure was conducted at 5 min, 1 h, 2 h, 3 h, 4 h, and 5 h after injection. On the basis of the data for these 4 patients (mean injected dose, 231 MBq), the radiation exposure of a (68)Ga-PSMA-617 PET/CT was identified.. Intense tracer uptake was observed in the kidneys and salivary glands. In 14 of 19 patients (73.7%), at least 1 lesion suspected of being a tumor was detected at 3 h after injection. Of 53 representative tumor lesions selected at 3 h after injection, 47 lesions were visible at 1 h after injection. The mean tumor-to-background ratio for maximum standardized uptake value was 20.4 ± 17.3 (range, 2.3-84.0) at 1 h after injection and 38.2 ± 38.6 (range, 3.6-154.3) at 3 h after injection. The average radiation exposure (effective dose) was approximately 0.021 mSv/MBq.. Within healthy organs, the kidneys and salivary glands showed the highest (68)Ga-PSMA-617 uptake. The radiation exposure was relatively low. (68)Ga-PSMA-617 shows PCa lesions with high contrast. Images obtained between 2 and 3 h after injection seem to be the best option with regard to radiotracer uptake and tumor contrast. Later images can help to clarify unclear lesions.

Topics: Adult; Dipeptides; Edetic Acid; Gallium Isotopes; Gallium Radioisotopes; Heterocyclic Compounds, 1-Ring; Humans; Image Processing, Computer-Assisted; Kidney; Male; Middle Aged; Oligopeptides; Organometallic Compounds; Positron-Emission Tomography; Prostate-Specific Antigen; Prostatic Neoplasms; Radiometry; Radiopharmaceuticals; Salivary Glands; Theranostic Nanomedicine; Tissue Distribution