Synthesis, Quality Control, and Bench-to-Bed Translation of a New [68Ga]Ga-Labeled NOTA-Conjugated Bisphosphonate for Imaging Skeletal Metastases by Positron Emission Tomography.

Background: Early detection of skeletal metastasis is of great interest to determine the prognosis of cancer. Positron emission tomography-computed tomography (PET-CT) imaging provides a better temporal and spectral resolution than single photon emission computed tomography-computed tomography (SPECT-CT) imaging, and hence is more suitable to detect small metastatic lesions. Although [18F]NaF has been approved by U.S. FDA for a similar purpose, requirement of a medical cyclotron for its regular formulation restricts its extensive utilization. Efforts have been made to find suitable alternative molecules that can be labeled with 68Ga and used in PET-CT imaging. Objective: The main objective of this study is to synthesize and evaluate a new [68Ga]Ga-labeled NOTA-conjugated geminal bisphosphonate for its potential use in early detection of skeletal metastases using PET-CT. Methods: The authors performed a multistep synthesis of a new NOTA-conjugated bisphosphonic acid using thiourea linker and radiolabeled the molecule with 68Ga. The radiolabeled formulation was evaluated for its in vitro stability, affinity for hydroxyapatite (HA) particles, preclinical biodistribution in animal models, and PET-CT imaging in patients. Results: The bifunctional chelator (NOTA)-conjugated bisphosphonate was synthesized with 97.8% purity and radiolabeled with 68Ga in high yield (>98%). The radiolabeled formulation was found to retain its stability in vitro to the extent of >95% up to 4 h in physiological saline and human serum. The formulation also showed high affinity for HA particles in vitro with Kd = 907 ± 14 mL/g. Preclinical biodistribution studies in normal Wistar rats demonstrated rapid and almost exclusive skeletal accumulation of the complex. PET-CT imaging in a patient confirmed its ability to detect small metastatic skeletal lesions. Conclusions: The newly synthesized [68Ga]Ga-labeled NOTA-conjugated bisphosphonate is a promising radiotracer for PET-CT imaging for skeletal metastases.

A cost effective method for the preparation of sodium fluoride [18F]NaF for PET-CT imaging by using an in-house designed module.

We report the development of a manual module for the preparation of [18F]NaF for metastatic bone cancer imaging. By using this simple module, [18F]NaF production can be carried out inexpensively without using commercially available kits. The module can be used for making [18F]NaF from freshly irradiated H218O water or with left over activity in the target after [18F]FDG production. The product meets all quality control parameters.

Preparation of Patient Doses of [177Lu]Lu-DOTATATE and [177Lu]Lu-PSMA-617 with Carrier Added (CA) and No Carrier Added (NCA) 177Lu.

Purpose: [177Lu]Lu-DOTATATE and [177Lu]Lu-PSMA-617 used for targeted radionuclide therapy are very often prepared in the hospital radiopharmacy. The preparation parameters vary depending upon the specific activity of the 177Lu used. The aim of this study was to develop optimized protocols to be used in the nuclear medicine department for the preparation of patient doses of the above radiopharmaceuticals. Method: 177Lu (CA and NCA) were used for radiolabeling DOTATATE and PSMA-617. Parameters studied are 177Lu of different specific activity and different peptide concentrations and two different buffer systems. Paper and thin layer chromatography systems were used for estimating the radiochemical yield as well as radiochemical purity. Solid-phase extraction was used for the purification of the labeled tracers. Results: [177Lu]Lu-DOTATATE was prepared with CA 177Lu (n = 13) and NCA177Lu (n = 6). Four batches each of [177Lu]Lu-PSMA-617 were prepared using CA and NCA 177Lu. Radiochemical yields > 80% and final product with less than < 1% radiochemical impurity could be obtained in all batches which were used for therapy. Conclusion: Robust protocols for the preparation of clinical doses of [177Lu]Lu-DOTATATE and [177Lu]Lu-PSMA-617 were developed and used for the preparation of clinical doses. The quality of the SPECT images of both the tracers are consistent with the expected uptake in respective diseases.

Experience of 6-l-[18F]FDOPA Production Using Commercial Disposable Cassettes and an Automated Module.

Purpose: The clinical demand of 6-l-[ 18F] FDOPA is gaining rapidly for imaging neurodegenerative diseases by using positron emission tomography. Hence, large-scale production of 6-l-[18F] FDOPA is necessary. This paper describes our experience on the production of 6-l-[18F]FDOPA via nucleophilic synthesis using NEPTIS module and a commercially available cassette based chemistry. Method: 6-l-[18F]FDOPA production could be completed in three synthetic steps by using ABX nitro precursor. The precursor is first labeled with18F by replacing a -NO2 leaving group followed by purification using a solid phase cartridge. In the subsequent step, the radiolabeled precursor is oxidized using meta chloroperoxy benzoic acid hydrolyzed to remove the four different protecting groups. The product is finally purified in a series of solid phase cartridges to yield radiochemically pure 6-l-[18F]FDOPA. Results: Total 36 batches of 6-l-[18F]FDOPA were produced. The decay uncorrected yield were 5.5 ± 1.5% (n = 33) which corresponds to a decay corrected yield of 11.8 ± 3.2% (n = 33). The radiochemical purity of the product obtained is always > 95%. Conclusion: The yields obtained are low and hence there is a need to improve synthetic chemistry. In order to understand the efficiency of each step, a detailed analysis using the radioactive traces obtained from the automated module was carried out. The radiolabeling yield of precursor is only about 50% and there is subsequent reduction in activity in the oxidation as well as hydrolysis steps. Despite the low radiochemical yields, the product obtained was suitable for imaging.

68Ga-PSMA PET/CT Imaging in Multiple Myeloma.

The potential applications of Ga-labeled prostate-specific membrane antigen (PSMA) PET/CT in the imaging of prostate cancer are now well established. A few case reports regarding the potential use of Ga-PSMA PET/CT in nonprostate cancer malignancies are also published. Apparently, the tumor neoangiogenesis is the mechanism attributed to increased Ga-PSMA uptake in the tumor sites in nonprostatic malignancies. We describe the use of Ga-PSMA PET/CT in imaging multiple myeloma. The intense Ga-PSMA avidity of the lesions also opens up the possibility of theranostics with Lu-PSMA.

Diagnostic Value of 68Ga PSMA-11 PET/CT Imaging of Brain Tumors-Preliminary Analysis.

OBJECTIVE: To evaluate the feasibility of using Ga PSMA-11 PET/CT for imaging brain lesions and its comparison with F-FDG. METHODS: Ten patients with brain lesions were included in the study. Five patients were treated cases of glioblastoma with suspected recurrence. F-FDG and Ga PSMA-11 brain scans were done for these patients. Five patients were sent for assessing the nature (primary lesion/metastasis) of space occupying lesion in brain. They underwent whole body F-FDG PET/CT scan and a primary site elsewhere in the body was ruled out. Subsequently they underwent Ga PSMA-11 brain PET/CT imaging. Target to background ratios (TBR) for the brain lesions were calculated using contralateral cerebellar uptake as background. RESULTS: In five treated cases of glioblastoma with suspected recurrence the findings of Ga PSMA-11 PET/CT showed good correlation with that of F-FDG PET/CT scan. Compared to the F-FDG, Ga PSMA-11 PET/CT showed better visualization of the recurrent lesion (presence/absence) owing to its significantly high TBR. Among the five cases evaluated for lesion characterization glioma and atypical meningioma patients showed higher SUVmax in the lesion with Ga PSMA-11 than with F-FDG and converse in cases of lymphoma. TBR was better with Ga PSMA PET/CT in all cases. CONCLUSION: Ga PSMA-11 PET/CT brain imaging is a potentially useful imaging tool in the evaluation of brain lesions. Absence of physiological uptake of Ga PSMA-11 in the normal brain parenchyma results in high TBR values and consequently better visualization of metabolically active disease in brain.

68Ga-DOTA Ubiquicidin PET/CT in an Infected Implant.

We describe the case of a 55-year-old man who presented with history of fever for 3 months that began 2 months after he had undergone open reduction and internal fixation of left humerus fracture. Implant infection was suspected, but conventional imaging remained unyielding. Ga-DOTA ubiquicidin PET/CT showed increased tracer uptake along the entire length of the implant in the left humerus. Implant removal and temporary external fixation were done. In 24 hours, the patient became afebrile, and blood culture on the fourth day was sterile.

Complimentary Pattern of Uptake in 18F-FDG PET/CT and 68Ga-Prostate-Specific Membrane Antigen PET/CT in a Case of Metastatic Clear Cell Renal Carcinoma.

We describe a case of metastatic clear cell renal cell carcinoma with intensely tracer concentrating lesions in left suprarenal region, mediastinal lymph nodes, lytic bone lesions, thyroid nodules, and mild abnormal tracer-avid lung nodules in Ga-prostate-specific membrane antigen (PSMA) PET/CT. On the other hand F-FDG PET/CT showed mild to no significant abnormal uptake in these lesions. Complimentary uptake pattern was observed in Ga-PSMA and F-FDG PET images in thyroid lesions and D5 vertebral lesion. This case highlights the possibilities of imaging clear cell renal cell carcinoma with Ga-PSMA and opens the possibility of treatment with Lu-PSMA.

Radiolabeled enzyme inhibitors and binding agents targeting PSMA: Effective theranostic tools for imaging and therapy of prostate cancer.

Because of the broad incidence, morbidity and mortality associated with prostate-derived cancer, the development of more effective new technologies continues to be an important goal for the accurate detection and treatment of localized prostate cancer, lymphatic involvement and metastases. Prostate-specific membrane antigen (PSMA; Glycoprotein II) is expressed in high levels on prostate-derived cells and is an important target for visualization and treatment of prostate cancer. Radiolabeled peptide targeting technologies have rapidly evolved over the last decade and have focused on the successful development of radiolabeled small molecules that act as inhibitors to the binding of the N-acetyl-l-aspartyl-l-glutamate (NAAG) substrate to the PSMA molecule. A number of radiolabeled PSMA inhibitors have been described in the literature and labeled with SPECT, PET and therapeutic radionuclides. Clinical studies with these agents have demonstrated the improved potential of PSMA-targeted PET imaging agents to detect metastatic prostate cancer in comparison with conventional imaging technologies. Although many of these agents have been evaluated in humans, by far the most extensive clinical literature has described use of the 68Ga and 177Lu agents. This review describes the design and development of these agents, with a focus on the broad clinical introduction of PSMA targeting motifs labeled with 68Ga for PET-CT imaging and 177Lu for therapy. In particular, because of availability from the long-lived 68Ge (T1/2=270days)/68Ga (T1/2=68min) generator system and increasing availability of PET-CT, the 68Ga-labeled PSMA targeted agent is receiving widespread interest and is one of the fastest growing radiopharmaceuticals for PET-CT imaging.

68Ga-PSMA PET/CT False-Positive Tracer Uptake in Paget Disease.

65-year-old man with left-sided pelvic pain on evaluation was found to have features suggestive of either Paget disease or prostatic bone metastasis of the left hemipelvis based on Tc-MDP bone scan and MRI. Ga-PSMA PET/CT to assess the possibility of primary prostate cancer and if present to stage it helped to rule out prostate cancer because of absence of focal abnormal increased tracer uptake in the prostate gland. However, false-positive tracer uptake was noted in the left hemipelvis, which was subject to biopsy and histopathologically proven to be Paget disease involvement.

Preparation of [(68)Ga]PSMA-11 for PET-CT imaging using a manual synthesis module and organic matrix based (68)Ge/(68)Ga generator.

INTRODUCTION: [(68)Ga]PSMA-11 is a relatively recently introduced radiopharmaceutical for PET-CT imaging of prostate cancer patients. The availability of (68)Ge/(68)Ga generator and PSMA-11 ligand from commercial sources is facilitating the production of the radiopharmaceutical in-house. This paper describes our experience on the preparation of ~200 batches of [(68)Ga]PSMA-11 for conducting PET-CT imaging in patients suspected/suffering from prostate cancer. METHODS: The radiosynthesis of [(68)Ga]PSMA-11 was done in a hospital based nuclear medicine department using (68)Ge/(68)Ga generator and a manual synthesis module, both supplied by Isotope Technologies Garching (ITG), Germany. The production involved the reaction of 5µg (5.3nmol) of PSMA-11 ligand in 1 ml of 0.25M sodium acetate buffer with 4ml of (68)GaCl3 in 0.05M HCl for 5min at 105°C; followed by purification in a C18 cartridge and collection through a 0.22µm pore size filter. RESULTS: The radiochemical yields obtained were consistently high, 93.19%±3.76%, and there was hardly any batch failure. The radiochemical purity of the product was >99% and the product was stable for over 2h; however it was used in patients immediately after preparation. About 200 batches of [(68)Ga]PSMA-11 were prepared during the period and more than 300 patients received the tracer during the 14months of study. No adverse reaction was observed in any of the patients and the image qualities were consistent with literature reports. CONCLUSION: [(68)Ga]PSMA-11 with high radiochemical and radionuclidic purity is conveniently prepared by using a (68)Ge/(68)Ga generator and manual synthesis module. The radiochemical yields are very high; and activity sufficient for 3-4 patients can be prepared in a single batch; multiple batches can be done on the same day and when needed after a gap of 1.5-2h.

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.