Preclinical investigations and first-in-human application of 152Tb-PSMA-617 for PET/CT imaging of prostate cancer.

BACKGROUND: For almost a decade, terbium radioisotopes have been explored for their potential theragnostic application in nuclear medicine: 152Tb and 155Tb are the radioisotopes identified for PET or SPECT imaging, while 149Tb and 161Tb have suitable decay characteristics for α- and combined ß-/Auger-e--therapy, respectively. In the present study, the application of 152Tb, in combination with PSMA-617 for imaging of prostate-specific membrane antigen (PSMA)-positive prostate cancer, was demonstrated in a preclinical setting and in a patient with metastatic castration-resistant prostate cancer (mCRPC). RESULTS: 152Tb was produced at the ISOLDE facility at CERN/Geneva, Switzerland, by spallation, followed by on-line mass separation. The chemical separation was performed at Paul Scherrer Institute using chromatographic methods, as previously reported. 152Tb was employed for labeling PSMA-617, and the radioligand was extensively investigated in vitro to demonstrate similar characteristics to its 177Lu-labeled counterpart. Preclinical PET/CT imaging studies performed with mice enabled visualization of PSMA-positive PC-3 PIP tumors, while uptake in PSMA-negative PC-3 flu tumors were absent. Based on these promising preclinical results, 152Tb was shipped to Zentralklinik Bad Berka, Germany, where it was used for labeling of PSMA-617, enabling PET imaging of a patient with mCRPC. PET/CT scans were performed over a period of 25 h post injection (p.i.) of the radioligand (140 MBq). The images were of diagnostic quality, particularly those acquired at later time points, and enabled the detection of the same metastatic lesions and of local recurrent tumor as previously detected by 68Ga-PSMA-11 PET/CT acquired 45 min p.i. CONCLUSIONS: The results of this study demonstrate the successful preparation and preclinical testing of 152Tb-PSMA-617 and its first application in a patient with mCRPC. This work could pave the way towards clinical application of other Tb radionuclides in the near future, most importantly 161Tb, which has promising decay characteristics for an effective treatment of mCRPC patients.

Clinical evaluation of the radiolanthanide terbium-152: first-in-human PET/CT with 152Tb-DOTATOC.

The existence of theragnostic pairs of radionuclides allows the preparation of radiopharmaceuticals for diagnostic and therapeutic purposes. Radiolanthanides, such as 177Lu, are successfully used for therapeutic purposes; however, a perfect diagnostic match is currently not available for clinical use. A unique, multi-disciplinary study was performed using 152Tb (T1/2 = 17.5 h, Eß+average = 1140 keV, Iß+ = 20.3%), which resulted in the first-in-human PET/CT images with this promising radionuclide. For this purpose, 152Tb was produced via a spallation process followed by mass separation at ISOLDE, CERN. The chemical separation and quality control, performed at PSI, resulted in a pure product in sufficient yields. Clinical PET phantom studies revealed an increased image noise level, because of the smaller ß+ branching ratio of 152Tb as compared to standard PET nuclides at matched activity concentrations; however, the expected recovery would be comparable at matched signal-to-noise ratios in clinical PET. 152Tb was used for labeling DOTATOC, at Zentralklinik Bad Berka, and administered to a patient for a first-in-human clinical study. PET scans were performed over a period of 24 h, allowing the visualization of even small metastases with increased tumor-to-background contrast over time. Based on the results obtained in this work, it can be deduced that PET/CT imaging with 152Tb-labeled targeting agents has promise for clinical application and may be particularly interesting for pre-therapeutic dosimetry.

Radioguided surgery in neuroendocrine tumors using Ga-68-labeled somatostatin analogs: a pilot study.

BACKGROUND: Previous studies of the intraoperative use of a hand-held gamma probe to localize metastases and primary tumors have shown improved assessment of tumor spread and changes in surgical management based on additional information gained by radioguided surgery (RGS). PURPOSE: The aim was to test the feasibility and advantages of doing RGS using a gallium-68 labeled with somatostatin receptor analogs in the intraoperative detection of neuroendocrine tumors. METHODS: Ga-68 somatostatin receptor PET/CT imaging was performed preoperatively in 9 patients with gastroenteropancreatic neuroendocrine tumors. Statistical analyses were performed to find out the correlation between the pathologic size of the tumor lesions and the maximum standardized uptake value on PET/CT as well as the target/nontarget ratio (T/NT) of gamma probe counts. Thereafter, the impact of the planned operation procedure and the lesion-based sensitivity of tumor detection (surgical palpation vs. PET/CT vs. gamma probe) had been observed. RESULTS: Overall, 72 locations in 9 patients were examined intraoperatively using gamma probes. The gamma probe detected 94% of the whole histologically quantified lesions, whereas the PET/CT allocated 69% and surgical palpation, 50%. RGS resulted in change in the operative procedure in 56%. There was a significant correlation between the maximum standardized uptake value and tumor size (0.74; P < 0.005). CONCLUSION: Hand-held gamma probe surgery using gallium-68-labeled somatostatin analogs is a feasible and an attractive option for real-time detection of small metastases and primaries of neuroendocrine tumors.

Results of individual patient dosimetry in peptide receptor radionuclide therapy with 177Lu DOTA-TATE and 177Lu DOTA-NOC.

UNLABELLED: One of the few treatment options for inoperable neuroendocrine tumors (NET) is peptide receptor radiotherapy with somatostatin analogs. In this study, we compared the dosimetric parameter uptake, half-life (kinetics), and mean absorbed organ and tumor doses of (177)Lu DOTA-NOC and (177)Lu DOTA-TATE. METHODS: Ninety-five (95) post-therapeutic dosimetric assessments using (177)Lu DOTA-TATE and 8 using (177)Lu DOTA-NOC in 69 patients with neuroendocrine tumors with high somatostatin receptor expression (verified by Ga-68 DOTA-NOC positron emission tomography/computed tomography) were analyzed. Dosimetric calculations were performed according to the Medical Internal Radiation Dose scheme. RESULTS: (177)Lu DOTA-NOC showed a significantly (p < or = 0.05; sign test) higher uptake for whole-body and normal tissue, as compared to (177)Lu DOTA-TATE, leading to a significant higher whole-body dose of 0.07 mGy/ MBq for DOTA-NOC, as compared to 0.05 mGy/MBq for DOTA-TATE. Renal and spleen uptake and radiation doses were not significantly higher for DOTA-NOC. The uptake in tumor lesions and the mean absorbed tumor dose were higher for DOTA-TATE. The red marrow dose was approximately 0.2 Gy. CONCLUSIONS: Our first results demonstrated that the higher in vitro affinity of DOTA-NOC leads to a higher uptake in normal tissues and, therefore, to an increase in the whole-body dose. The high interpatient variability of these results makes an individual patient dosimetry obligatory.