Optimised production of technetium-94m for PET imaging by proton-irradiation of phosphomolybdic acid in cyclotron liquid target.

Natural-abundance phosphomolybdic acid (H3(Mo12PO40) ‧12H2O, 0.181-0.552 g Mo/mL) solutions were irradiated with 12.9 MeV protons on a GE PETtrace cyclotron using an adapted standard liquid target. Technetium-94m (94mTc) was produced through the 94Mo(p,n)94mTc nuclear reaction with saturation yields of up to 53 ± 6 MBq/µA. End of bombardment activities of 161 ± 17 MBq and 157 ± 7 MBq were achieved for the 0.552 g Mo/mL solution (10 µA for 30 min) and 0.181 g Mo/mL solution (15 µA for 60 min), respectively. No visible degradation of the niobium target body and foil were seen during the irradiations of up to 15 µA for 60 min. The produced 94mTc was separated from the target phosphomolybdic acid solution with >98% recovery using an aqueous biphasic extraction resin. Compared to previous reported liquid target methods for 94mTc production, the better production yield, in-target solution stability during irradiation and 94mTc separation recovery of phosphomolybdic acid makes it a very promising target material for routine clinical 94mTc production at medical facilities with liquid targets already installed for 18F production.

Microwave-assisted synthesis of [52Mn]Mn-porphyrins: Applications in cell and liposome radiolabelling.

BACKGROUND: Manganese porphyrins have several therapeutic/imaging applications, including their use as radioprotectants (in clinical trials) and as paramagnetic MRI contrast agents. The affinity of porphyrins for lipid bilayers also makes them candidates for cell/liposome labelling. We hypothesised that metalation with the positron emission tomography (PET) radionuclide 52Mn (t1/2 = 5.6 d) would allow long-term in vivo biodistribution studies of Mn-porphyrins, as well as a method to label and track cells/liposomes, but methods for fast and efficient radiolabelling are lacking. RESULTS: Several porphyrins were produced and radiolabelled by addition to neutralised [52Mn]MnCl2 and heating using a microwave (MW) synthesiser, and compared with non-MW heating. MW radiosynthesis allowed >95 % radiochemical yields (RCY) in just 1 h. Conversely, non-MW heating at 70 °C for 1 h resulted in low RCY (0-25 % RCY) and most porphyrins did not reach radiolabelling completion after 24 h. Formation of the 52Mn-complexes were confirmed with radio-HPLC by comparison with their non-radioactive 55Mn counterparts. Following this, several [52Mn]Mn-porphyrins were used to radiolabel liposomes resulting in 75-86 % labelling efficiency (LE). Two lead [52Mn]Mn-porphyrins were taken forward to label MDA-MB-231 cancer cells in vitro, achieving ca. 11 % LE. After 24 h, 32-45 % of the [52Mn]Mn-porphyrins was retained in cells. CONCLUSIONS: In contrast to standard methods, MW heating allows the fast synthesis of [52Mn]Mn-porphyrins with >95 % radiochemical yields that avoid purification. [52Mn]Mn-porphyrins also show promising cell/liposome labelling properties. Our reported technique can potentially be exploited for the in vivo imaging of Mn-porphyrin therapeutics, as well as for the accurate in vivo quantification of Mn-porphyrin MRI agents.

Preclinical evaluation of potential infection-imaging probe [68 Ga]Ga-DOTA-K-A9 in sterile and infectious inflammation.

The development of bacteria-specific infection radiotracers is of considerable interest to improve diagnostic accuracy and enabling therapy monitoring. The aim of this study was to determine if the previously reported radiolabelled 1,4,7,10-tetraazacyclododecane-N,N',N″,N‴-tetraacetic acid (DOTA) conjugated peptide [68 Ga]Ga-DOTA-K-A9 could detect a staphylococcal infection in vivo and distinguish it from aseptic inflammation. An optimized [68 Ga]Ga-DOTA-K-A9 synthesis omitting the use of acetone was developed, yielding 93 ± 0.9% radiochemical purity. The in vivo infection binding specificity of [68 Ga]Ga-DOTA-K-A9 was evaluated by micro positron emission tomography/magnetic resonance imaging of 15 mice with either subcutaneous Staphylococcus aureus infection or turpentine-induced inflammation and compared with 2-deoxy-2-[18 F]fluoro-D-glucose ([18 F]FDG). The scans showed that [68 Ga]Ga-DOTA-K-A9 accumulated in all the infected mice at injected doses ≥3.6 MBq. However, the tracer was not found to be selective towards infection, since the [68 Ga]Ga-DOTA-K-A9 also accumulated in mice with inflammation. In a concurrent in vitro binding evaluation performed with a 5-carboxytetramethylrhodamine (TAMRA) fluorescence analogue of the peptide, TAMRA-K-A9, the microscopy results suggested that TAMRA-K-A9 bound to an intracellular epitope and therefore preferentially targeted dead bacteria. Thus, the [68 Ga]Ga-DOTA-K-A9 uptake observed in vivo is presumably a combination of local hyperemia, vascular leakiness and/or binding to an epitope present in dead bacteria.

A Comprehensive Safety Evaluation of 68Ga-Labeled Ligand Prostate-Specific Membrane Antigen 11 PET/CT in Prostate Cancer: The Results of 2 Prospective, Multicenter Trials.

PURPOSE: The aim of this study was to evaluate the clinical safety profile of the Ga-PSMA-11 ligand for PET/CT imaging in prospective clinical trials. METHODS: Eighty-eight patients with newly diagnosed or recurrent prostate cancer participated in 2 prospective trials. Safety reporting was identical in the 2 trials. The Ga-PSMA-11 ligand was administered as 2 MBq/kg body weight (mean, 9.2 µg, 9.7 nmol). The reporting of clinical adverse events (AEs) and the measurement of blood pressure (BP) and heart rate (HR) were performed prior to injection (baseline); immediately after injection of Ga-PSMA-11 (postinjection); at 1, 10, and 60 minutes after injection; and after acquisition of the PET/CT scan (postscan). All hemodynamic assessments were performed in the supine position, except for the postscan measurement (sitting). The patients were interviewed regarding any AEs at baseline, postinjection, or postscan. In addition, the patients were instructed to report any AEs during the investigation and to contact the investigator if AEs occurred during the rest of the day. Adverse events were classified as mild, moderate, or severe by the patients and categorized by the investigator using the CTCAE (Common Terminology Criteria for Adverse Events) version 4.0. RESULTS: There were no reported clinical AEs. There were significant decreases in systolic BP (P < 0.001) and HR (P < 0.001) over time. In comparison, the diastolic BP increased significantly (P < 0.001). After removal of the last observation (supine position), there was no time-dependent change in systolic or diastolic BP, but the significant change in HR remained. The mean changes over the entire observation period were minimal (systolic BP, -6 to 5 mm Hg; diastolic BP, -2 to 3 mm Hg; HR, decrease of 5 beats/min). No patients developed hypotension. Fifty-five patients presented with hypertension at baseline, which increased by 1 CTCAE grade in 15 patients and by 2 grades in 2 patients. A large number of cases of asymptomatic (grade 1) bradycardia were observed, primarily in patients with preexisting bradycardia. One patient developed transient grade 1 tachycardia. No patients required medical intervention for cardiovascular perturbations. CONCLUSIONS: Ga-PSMA-11 PET/CT was very well tolerated. We consider Ga-PSMA-11 to be safe for human application.

(68)Ga-labeled phage-display selected peptides as tracers for positron emission tomography imaging of Staphylococcus aureus biofilm-associated infections: Selection, radiolabelling and preliminary biological evaluation.

INTRODUCTION: Staphylococcus aureus is a major cause of skin and deep-sited infections, often associated with the formation of biofilms. Early diagnosis and initiated therapy is essential to prevent disease progression and to reduce complications that can be serious. Imaging techniques are helpful combining anatomical with functional data in order to describe and characterize site, extent and activity of the disease. The purpose of the study was to identify and (68)Ga-label peptides with affinity for S. aureus biofilm and evaluate their potential as bacteria-specific positron emission tomography (PET) imaging agents. METHODS: Phage-displayed dodecapeptides were selected using an in vitro grown S. aureus biofilm as target. One cyclic (A8) and two linear (A9, A11) dodecapeptides were custom synthesized with 1,4,7,10-tetraazacyclododecane-N,N',N″,N‴-tetraacetic acid (DOTA) conjugated via a lysine linker (K), and for A11 also a glycine-serine-glycine spacer (GSG). The (68)Ga-labeling of A8-K-DOTA, A9-K-DOTA, and A11-GSGK-DOTA were optimized and in vitro bacterial binding was evaluated for (68)Ga-A9-K-DOTA and (68)Ga-A11-GSGK-DOTA. Stability of (68)Ga-A9-K-DOTA was studied in vitro in human serum, while the in vivo plasma stability was analyzed in mice and pigs. Additionally, the whole-body distribution kinetics of (68)Ga-A9-K-DOTA was measured in vivo by PET imaging of pigs and ex vivo in excised mice tissues. RESULTS: The (68)Ga-A9-K-DOTA and (68)Ga-A11-GSGK-DOTA remained stable in product formulation, whereas (68)Ga-A8-K-DOTA was unstable. The S. aureus binding of (68)Ga-A11-GSGK-DOTA and (68)Ga-A9-K-DOTA was observed in vitro, though blocking of the binding was not possible by excess of cold peptide. The (68)Ga-A9-K-DOTA was degraded slowly in vitro, while the combined in vivo evaluation in pigs and mice showed a rapid blood clearance and renal excretion of the (68)Ga-A9-K-DOTA. CONCLUSION: The preliminary in vitro and in vivo studies of the phage-display S. aureus biofilm-selected (68)Ga-A9-K-DOTA showed desirable features for a novel bacteria-specific imaging agent, despite of relative fast blood degradation in vivo.

Comparison of autologous (111)In-leukocytes, (18)F-FDG, (11)C-methionine, (11)C-PK11195 and (68)Ga-citrate for diagnostic nuclear imaging in a juvenile porcine haematogenous staphylococcus aureus osteomyelitis model.

The aim of this study was to compare (111)In-labeled leukocyte single-photon emission computed tomography (SPECT) and (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography (PET) to PET with tracers that potentially could improve detection of osteomyelitis. We chose (11)C-methionine, (11)C-PK11195 and (68)Ga-citrate and validated their diagnostic utility in a porcine haematogenous osteomyelitis model. Four juvenile 14-15 weeks old female pigs were scanned seven days after intra-arterial inoculation in the right femoral artery with a porcine strain of Staphylococcus aureus using a sequential scan protocol with (18)F-FDG, (68)Ga-citrate, (11)C-methionine, (11)C-PK11195, (99m)Tc-Nanocoll and (111)In-labelled autologous leukocytes. This was followed by necropsy of the pigs and gross pathology, histopathology and microbial examination. The pigs developed a total of five osteomyelitis lesions, five lesions characterized as abscesses/cellulitis, arthritis in three joints and five enlarged lymph nodes. None of the tracers accumulated in joints with arthritis. By comparing the 10 infectious lesions, (18)F-FDG accumulated in nine, (111)In-leukocytes in eight, (11)C-methionine in six, (68)Ga-citrate in four and (11)C-PK11195 accumulated in only one lesion. Overall, (18)F-FDG PET was superior to (111)In-leukocyte SPECT in marking infectious and proliferative, i.e. hyperplastic, lesions. However, leukocyte SPECT was performed as early scans, approximately 6 h after injection of the leukocytes, to match the requirements of the 18 h long scan protocol. (11)C-methionine and possibly (68)Ga-citrate may be useful for diagnosis of soft issue lesions.

Fast and simple one-step preparation of 68Ga citrate for routine clinical PET.

The imaging of infectious and inflammatory diseases using gallium-67 (67Ga) citrate scintigraphy has been a well-established diagnostic tool for decades. In recent times, interest has focused on PET using the short-lived positron emitting radioisotope 68Ga. 68Ga is not only more readily available, it also provides better quality images whose high resolution permits quantitative analyses, thus improving the management of patients suffering from infections or inflammation. The purpose of our study was to develop a fast and reliable synthesis protocol for the preparation of 68Ga citrate under good manufacturing practice aspects without the use of organic solvents. A commercially available synthesis module was used to perform 10 syntheses with an average yield of 768 ± 31 MBq (mean ± SD) within 10 min; 92.04 ± 1.23% of the radioactivity was located in the product vial, and the rest on the cation exchange cartridge (7.48 ± 1.23%) and in the waste vial (0.47 ± 0.28%). The radiochemical purity of the product determined by instant thin-layer chromatography was greater than 99%. The products have been proven to be sterile and pyrogen-free. Variations were made in several critical synthesis parameters, and the results are presented herein. By eliminating the use of organic solvents, the previously required quality control testing of the final product by gas chromatography can be abandoned. This novel, high-yielding method allows for a more efficient synthesis of 68Ga citrate with both shorter production time and high radiochemical purity.