Automatic radiosynthesis and preclinical evaluation of 18F-AlF-PSMA-NF as a potential PET probe for prostate cancer imaging.

Facile automatic production is important for the application of prostate-specific membrane antigen (PSMA) tracers in clinical practice. We developed a new 18F-AlF-labelled PSMA probe-18F-AlF-PSMA-NF-and explore its automated production method and potential value in clinical settings. 18F-AlF-PSMA-NF was prepared using an automated method with dimethylformamide (DMF) as the solvent in a positron emission tomography (PET)-MF-2 V-IT-I synthesizer. Tracer characteristics were examined both in vitro and in vivo. Micro-PET/computed tomography (CT) was performed to investigate the utility of 18F-AlF-PSMA-NF for imaging PSMA-positive tumours in vivo. 18F-AlF-PSMA-NF was prepared automatically within 35 min with a non-attenuation correction yield of 37.9 ± 11.2%. The tracer was hydrophilic, had a high affinity for PSMA (Kd = 2.58 ± 0.81 nM), and showed stability in both in vitro and in vivo conditions. In the cellular experiments, 18F-AlF-PSMA-NF uptake in PSMA-positive LNCaP cells was significantly higher than that in PSMA-negative PC-3 cells (P < 0.001), and could be blocked by excess ZJ-43-a PSMA inhibitor (P < 0.001). LNCaP tumours were clearly visualized by 18F-AlF-PSMA-NF on micro-PET/CT, with a high level of uptake (13.72 ± 2.01 percent injected dose per gram of tissue [%ID/g]) and high tumour/muscle ratio (close to 50:1). The PSMA-positive LNCaP tumours had a significantly higher uptake than PSMA-negative PC-3 tumours (13.72 ± 2.01%ID/g vs. 1.07 ± 0.48%ID/g, t = 10.382, P < 0.001), and could be blocked by ZJ-43 (13.72 ± 2.01%ID/g vs. 2.77 ± 1.44%ID/g, t = 8.14, P < 0.001). A new 18F-AlF-labelled PSMA probe-18F-AlF-PSMA-NF-was successfully developed and can be prepared automatically. It has the biological characteristics resembling that of a PSMA-based probe and can potentially be used in clinical settings.

Safety, Biodistribution, and Radiation Dosimetry of 18F-rhPSMA-7.3 in Healthy Adult Volunteers.

This first-in-humans study investigated the safety, biodistribution, and radiation dosimetry of a novel 18F-labeled radiohybrid prostate-specific membrane antigen (rhPSMA) PET imaging agent, 18F-rhPSMA-7.3. Methods: Six healthy volunteers (3 men, 3 women) underwent multiple whole-body PET acquisitions at scheduled time points up to 248 min after the administration of 18F-rhPSMA-7.3 (mean activity, 220; range, 210-228 MBq). PET scans were conducted in 3 separate sessions, and subjects were encouraged to void between sessions. Blood and urine samples were collected for up to 4 h after injection to assess metabolite-corrected radioactivity in whole blood, plasma, and urine. Quantitative measurements of 18F radioactivity in volumes of interest over target organs were determined directly from the PET images at 8 time points, and normalized time-activity concentration curves were generated. These normalized cumulated activities were then inputted into the OLINDA/EXM package to calculate the internal radiation dosimetry and the subjects' effective dose. Results:18F-rhPSMA-7.3 was well tolerated. One adverse event (mild headache, not requiring medication) was considered possibly related to 18F-rhPSMA-7.3. The calculated effective dose was 0.0141 mSv/MBq when using a 3.5-h voiding interval. The organs with the highest mean absorbed dose per unit of administered radioactivity were the adrenals (0.1835 mSv/MBq), the kidneys (0.1722 mSv/MBq), the submandibular glands (0.1479 mSv), and the parotid glands (0.1137 mSv/MBq). At the end of the first scanning session (mean time, 111 min after injection), an average of 7.2% (range, 4.4%-9.0%) of the injected radioactivity of 18F-rhPSMA-7.3 was excreted into urine. Conclusion: The safety, biodistribution, and internal radiation dosimetry of 18F-rhPSMA-7.3 are considered favorable for PET imaging.

An 18F-Labeled PSMA Ligand for PET/CT of Prostate Cancer: First-in-Humans Observational Study and Clinical Experience with 18F-JK-PSMA-7 During the First Year of Application.

In preclinical trials, the recently developed tracer 2-methoxy-18F-DCFPyL (18F-JK-prostate-specific membrane antigen [PSMA]-7) has shown favorable properties regarding clinical performance and radiochemical accessibility. The aim of this study was to evaluate the clinical utility of 18F-JK-PSMA-7 for PET/CT imaging of patients with prostate cancer. Methods: In an Institutional Review Board-approved pilot study, the initial clinical utility of PET/CT imaging with 18F-JK-PSMA-7 was directly compared with 68Ga-PSMA-11 PET/CT in a group of 10 patients with prostate cancer. The 2 PSMA tracers were administered to each patient less than 3 wk apart. Next, we analyzed the data of 75 consecutive patients who had undergone clinical 18F-JK-PSMA-7 PET/CT imaging for tumor localization of biochemical recurrence (BCR). Results: The pilot study in 10 patients who were examined with both PSMA tracers demonstrated that 18F-JK-PSMA-7 was at least equivalent to 68Ga-PSMA-11. All unequivocally 68Ga-PSMA-11-positive lesions could be also detected using 18F-JK-PSMA-7, and in 4 patients additional suspected PSMA-positive lesions were identified (1 patient changed from PSMA-negative to PSMA-positive). In patients with BCR (after prostatectomy or radiotherapy), the capacity of 18F-JK-PSMA-7 PET/CT to detect at least one PSMA-positive lesion was 84.8%. The prostate-specific antigen (PSA)-stratified detection rate of 18F-JK-PSMA-7 after prostatectomy varied among 54.5% (6/11 patients; PSA < 0.5 µg/L), 87.5% (14/16 patients; PSA 0.5-2 µg/L), and 90.9% (20/22 patients; PSA > 2 µg/L). Conclusion: The tracer 18F-JK-PSMA-7 was found to be safe and clinically useful. We demonstrated that 18F-JK-PSMA-7 was not inferior when directly compared with 68Ga-PSMA-11 in a pilot study but indeed identified additional PSMA-avid suspected lesions in oligometastasized patients with BCR. In a subsequent analysis of a clinical cohort of BCR patients, 18F-JK-PSMA-7 was useful in tumor localization. 18F-JK-PSMA-7 is recommended for future prospective trials.

Integrated 68Ga-HBED-CC-PSMA-PET/MRI in patients with suspected recurrent prostate cancer.

AIM: Evaluate the diagnostic accuracy of 68Ga-labeled HBED-CC-PSMA-PET/MRI for detection of recurrent PCa in comparison to PET/CT. METHODS: 48 patients with suspected recurrent PCa underwent PET/CT after injection of the 68Ga-HBED-CC-PSMA ligand followed by integrated PET/MRI. Image analysis was performed by nuclear medicine physicians and radiologists with respect to the detection of lymph node metastases, bone metastases and local recurrence of the tumour. Image quality was evaluated visually based on a three-point ordinal scale. RESULTS: From 48 patients initially examined, 25 were finally eligible for qualitative and quantitative image evaluation. In 14 patients, neither PET/CT nor PET/MRI found tumour lesions, and 9 patients were excluded from image analysis due to a pronounced extinction artifact around the urinary bladder (halo). In comparison to 68Ga-HBED-CC-PSMA-PET/CT, 68Ga-HBED-CC-PSMA-PET/MRI identified 14 vs. 9 local recurrences in the prostate bed and 23 vs. 20 PET-positive lymph nodes, and 4 vs. 4 PET-positive bone lesions, respectively. While the improved detection of suspicious lymph nodes was primarily attributable to the PET component, the advantageous detection of tumour recurrences in the prostate bed was chiefly referable to the superior soft-tissue contrast of the MR component of integrated PET/MRI. Analysis of SUVmax revealed that 68Ga-HBED-CC-PSMA-PET/MRI provided significantly higher SUVmax compared to 68Ga-HBED-CC-PSMA-PET/CT (17.6, range 2.0-49.6, and 15.1, range 3.5-36.8, respectively, p = 0.0019). CONCLUSION: 68Ga-HBED-CC-PSMA-PET/MRI was found to be superior as compared to 68Ga-HBED-CC-PSMA-PET/CT in the detection of PSMA-expressing prostate bed recurrences.

Investigating the Effect of Ligand Amount and Injected Therapeutic Activity: A Simulation Study for 177Lu-Labeled PSMA-Targeting Peptides.

In molecular radiotherapy with 177Lu-labeled prostate specific membrane antigen (PSMA) peptides, kidney and/or salivary glands doses limit the activity which can be administered. The aim of this work was to investigate the effect of the ligand amount and injected activity on the tumor-to-normal tissue biologically effective dose (BED) ratio for 177Lu-labeled PSMA peptides. For this retrospective study, a recently developed physiologically based pharmacokinetic model was adapted for PSMA targeting peptides. General physiological parameters were taken from the literature. Individual parameters were fitted to planar gamma camera measurements (177Lu-PSMA I&T) of five patients with metastasizing prostate cancer. Based on the estimated parameters, the pharmacokinetics of tumor, salivary glands, kidneys, total body and red marrow was simulated and time-integrated activity coefficients were calculated for different peptide amounts. Based on these simulations, the absorbed doses and BEDs for normal tissue and tumor were calculated for all activities leading to a maximal tolerable kidney BED of 10 Gy2.5/cycle, a maximal salivary gland absorbed dose of 7.5 Gy/cycle and a maximal red marrow BED of 0.25 Gy15/cycle. The fits yielded coefficients of determination > 0.85, acceptable relative standard errors and low parameter correlations. All estimated parameters were in a physiologically reasonable range. The amounts (for 25-29 nmol) and pertaining activities leading to a maximal tumor dose, considering the defined maximal tolerable doses to organs of risk, were calculated to be 272±253 nmol (452±420 µg) and 7.3±5.1 GBq. Using the actually injected amount (235±155 µg) and the same maximal tolerable doses, the potential improvement for the tumor BED was 1-3 fold. The results suggest that currently given amounts for therapy are in the appropriate order of magnitude for many lesions. However, for lesions with high binding site density or lower perfusion, optimizing the peptide amount and activity might improve the tumor-to-kidney and tumor-to-salivary glands BED ratio considerably.

Biodistribution and radiation dosimetry of (68)Ga-PSMA HBED CC-a PSMA specific probe for PET imaging of prostate cancer.

PURPOSE: Positron emission tomography (PET) agents targeting the prostate-specific membrane antigen (PSMA) are currently under broad clinical and scientific investigation. (68)Ga-PSMA HBED-CC constitutes the first (68)Ga-labelled PSMA-inhibitor and has evolved as a promising agent for imaging PSMA expression in vivo. The aim of this study was to evaluate the whole-body distribution and radiation dosimetry of this new probe. METHODS: Five patients with a history or high suspicion of prostate cancer were injected intravenously with a mean of 139.8 ± 13.7 MBq of (68)Ga-PSMA HBED-CC (range 120-158 MBq). Four static skull to mid-thigh scans using a whole-body fully integrated PET/MR-system were performed 10 min, 60 min, 130 min, and 175 min after the tracer injection. Time-dependent changes of the injected activity per organ were determined. Mean organ-absorbed doses and effective doses (ED) were calculated using OLINDA/EXM. RESULTS: Injection of a standard activity of 150 MBq (68)Ga-PSMA HBED-CC resulted in a median effective dose of 2.37 mSv (Range 1.08E-02 - 2.46E-02 mSv/MBq). The urinary bladder wall (median absorbed dose 1.64E-01 mGv/MBq; range 8.76E-02 - 2.91E-01 mGv/MBq) was the critical organ, followed by the kidneys (median absorbed dose 1.21E-01 mGv/MBq; range 7.16E-02 - 1.75E-01), spleen (median absorbed dose 4.13E-02 mGv/MBq; range 1.57E-02 - 7.32E-02 mGv/MBq) and liver (median absorbed dose 2.07E-02 mGv/MBq; range 1.80E-02 - 2.57E-02 mGv/MBq). No drug-related pharmacological effects occurred. CONCLUSION: The use of (68)Ga-PSMA HBED-CC results in a relatively low radiation exposure, delivering organ doses that are comparable to those of other (68)Ga-labelled PSMA-inhibitors used for PET-imaging. Total effective dose is lower than for other PET-agents used for prostate cancer imaging (e.g. (11)C- and (18)F-Choline).

68Ga-PSMA PET/CT Imaging and 153Sm-EDTMP Bone Pain Palliation Therapy.

Ga-labeled prostate-specific membrane antigen (PSMA) is a potential tool in the imaging of recurrent prostate cancer. Ga-PSMA imaging is also useful for radiotherapy planning and in targeted therapy with Lu-PSMA. A few case reports regarding the use of Ga-PSMA in nonprostate cancer malignancies are also reported. We describe the use of Ga-PSMA imaging before Sm-EDTMP bone pain palliation therapy in a 58-year-old hormone refractory prostate cancer patient with extensive bone metastases.

A low molecular weight PSMA-based fluorescent imaging agent for cancer.

We synthesized YC-27 3 to provide a fluorescent imaging agent for the prostate-specific membrane antigen (PSMA), a marker for hormone-independent prostate cancer and tumor neovasculature, with suitable pharmacokinetics for use in vivo. Immediate precursor trifluoroacetate salt of 2-(3-{5-[7-(5-amino-1-carboxy-pentylcarbamoyl)-heptanoylamino]-1-carboxy-pentyl}-ureido)-pentanedioic acid 2 was conjugated with a commercially available near-infrared light-emitting dye (IRDye 800CW) to provide 3 in 72% yield. YC-27 3 demonstrated a PSMA inhibitory activity of 0.37nM and was capable of generating target-to-nontarget ratios of at least 10 in PSMA-expressing PC3-PIP vs. PSMA-negative PC3-flu tumors in vivo. YC-27 3 may be useful for study of PSMA-expressing tissue in preclinical models or for intraoperative guidance.

Cell-Surface labeling and internalization by a fluorescent inhibitor of prostate-specific membrane antigen.

BACKGROUND: [corrected] Prostate-specific membrane antigen (PSMA) remains an attractive target for imaging and therapeutic applications for prostate cancer. Recent efforts have been made to conjugate inhibitors of PSMA with imaging agents. Compared to antibodies, small-molecule inhibitors of PSMA possess apparent advantages for in vivo applications. To date, there are no reports on the cellular fate of such constructs once bound the extracellular domain of PSMA. The present study was focused on precisely defining the binding specificity, time-dependent internalization, cellular localization, and retention of inhibitor conjugates targeted to PSMA on LNCaP cells. A novel fluorescent inhibitor was prepared as a model to examine these processes. METHODS: Fluorescence microscopy of LNCaP and PC-3 cell lines was used to monitor the specificity, time-dependent internalization, cellular localization, and retention of a fluorescent PSMA inhibitor. RESULTS: Fluorescent inhibitor 2 was found to be a potent inhibitor (IC50 = 0.35 nM) of purified PSMA. Its high affinity for PSMA on living cells was confirmed by antibody blocking and competitive binding experiments. Specificity for LNCaP cells was demonstrated as no labeling by 2 was observed for negative control PC-3 cells. Internalization of 2 by viable LNCaP cells was detected after 30 min incubation at 37 degrees C, followed by accumulation in the perinuclear endosomes. It was noted that internalized fluorescent inhibitor can be retained within endosomes for up to 150 min without loss of signal. CONCLUSIONS: Our results suggest that potent, small-molecule inhibitors of PSMA can be utilized as carriers for targeted delivery for prostate cancer for future imaging and therapeutic applications.