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Purpose: Sotrovimab (VIR-7831), a human IgG1κ monoclonal antibody (mAb), binds to a conserved epitope on the SARS-CoV-2 spike protein receptor binding domain (RBD). The Fc region of VIR-7831 contains an LS modification to promote neonatal Fc receptor (FcRn)-mediated recycling and extend its serum half-life. Here, we aimed to evaluate the impact of the LS modification on tissue biodistribution, by comparing VIR-7831 to its non-LS-modified equivalent, VIR-7831-WT, in cynomolgus monkeys., Methods: 89 Zr-based PET/CT imaging of VIR-7831 and VIR-7831-WT was performed up to 14 days post injection. All major organs were analyzed for absolute concentration as well as tissue:blood ratios, with the focus on the respiratory tract, and a physiologically based pharmacokinetics (PBPK) model was used to evaluate the tissue biodistribution kinetics. Radiomics features were also extracted from the PET images and SUV values., Results: SUV mean uptake in the pulmonary bronchi for 89 Zr-VIR-7831 was statistically higher than for 89 Zr-VIR-7831-WT at days 6 (3.43 ± 0.55 and 2.59 ± 0.38, respectively) and 10 (2.66 ± 0.32 and 2.15 ± 0.18, respectively), while the reverse was observed in the liver at days 6 (5.14 ± 0.80 and 8.63 ± 0.89, respectively), 10 (4.52 ± 0.59 and 7.73 ± 0.66, respectively), and 14 (4.95 ± 0.65 and 7.94 ± 0.54, respectively). Though the calculated terminal half-life was 21.3 ± 3.0 days for VIR-7831 and 16.5 ± 1.1 days for VIR-7831-WT, no consistent differences were observed in the tissue:blood ratios between the antibodies except in the liver. While the lung:blood SUV mean uptake ratio for both mAbs was 0.25 on day 3, the PBPK model predicted the total lung tissue and the interstitial space to serum ratio to be 0.31 and 0.55, respectively. Radiomics analysis showed VIR-7831 had mean-centralized PET SUV distribution in the lung and liver, indicating more uniform uptake than VIR-7831-WT., Conclusion: The half-life extended VIR-7831 remained in circulation longer than VIR-7831-WT, consistent with enhanced FcRn binding, while the tissue:blood concentration ratios in most tissues for both drugs remained statistically indistinguishable throughout the course of the experiment. In the bronchiolar region, a higher concentration of 89 Zr-VIR-7831 was detected. The data also allow unparalleled insight into tissue distribution and elimination kinetics of mAbs that can guide future biologic drug discovery efforts, while the residualizing nature of the 89 Zr label sheds light on the sites of antibody catabolism., (© 2022. The Author(s).)

Vitamin H (biotin) is delivered to the fetus transplacentally by an active biotin-transport mechanism and is critical for fetal development. Our objective was to develop a comprehensive MRI technique for mapping biotin transporter activity in the murine placenta. Visualization of transporter activity can employ MRI's unique T 2 *-dependent signal 'off-switch', which is triggered by transporter mediated aggregation of biotinylated contrast agent (b-BSA-Gd-DTPA). MRI data were collected from pregnant mice after administration of b-BSA-Gd-DTPA and analyzed using a new sub-voxel biophysical signal model. Validation experiments included competition with native biotin, comparative tests using PET, histology, and ICPMS. MRI signal was governed by binding, aggregation, and clearance of biotin (confirmed by histology). Signal dynamics reflected the placenta's perfusion pattern modulated by biotin transporter activity and trophoblast mediated retention, and were in congruence with a three-compartment sub-voxel model. Pre-saturation of the transporters with free biotin suppressed b-BSA-Gd-DTPA uptake. The results were confirmed by PET, histology and ICPMS. The presented MRI-based platform allows to track activity of essential molecular transporters in the placenta, reflecting a transporter-mediated uptake, followed by retention and aggregation, and recycling associated with the large b-BSA-Gd-DTPA conjugate. The presented DCE-MRI technique can furthermore be used to map and characterize microstructural compartmentation and transporter activity without exposing the fetus to contrast media.

Molecular probes targeting bacteria provide opportunities to target bacterial infections in vivo for both imaging and therapy. In the current study, we report the development of positron emission tomography (PET) probes for imaging of live bacterial infection based on the small molecules HLys-DOTA, a polycationic peptide synthesized as the D-isomer (RYWVAWRNRG) conjugated to 1, 4, 7, 10-tetraazacyclododecane-N',N″,N‴,N-tetraacetic acid (DOTA) and AB1-HLys-DOTA, which includes an unnatural amino acid AB1 that preferentially binds to bacteria membrane lipids with amine groups via formation of iminoboronates. HLys-DOTA and AB1-HLys-DOTA peptides were radiolabeled with 64 Cu and investigated as PET imaging agents to track bacterial infection in vitro and in intramuscularly infected (IM) mice models. Cell uptake studies at 37°C in Staphylococcus aureus (SA) show higher uptake of 64 Cu-AB1-HLys-DOTA; 98.47 ± 3.54% vs 64 Cu-HLys-DOTA; 39.12 ± 3.27% at 24 h. Standard uptake values (SUV) analysis of the PET images resulted in mean SUV of 0.70 ± 0.08, 0.49 ± 0.04, and 0.31 ± 0.01 for 64 Cu-AB1-HLys-DOTA and 0.17 ± 0.06, 0.16 ± 0.02, and 0.13 ± 0.01 for 64 Cu-HLys-DOTA at 1, 4, and 24 h post injection, respectively, in the infected muscles. Similarly, in the biodistribution studies, dose uptake in the infected muscles was 4 times higher in the targeted 64 Cu-AB1-HLys-DOTA group than in the 64 Cu-HLys-DOTA group and 2-3 times higher than in the PBS control group at 1, 4, and 24 h post injection. 64 Cu-AB1-HLys-DOTA was able to distinguish between SA-infected muscle and Pseudomonas aeruginosa (PA) infected muscle with lower mean SUV of 0.28 ± 0.10 at 1 h post injection. This illustrates the utility of the AB1 covalently targeting group in synergy with the HLys peptide, which noncovalently binds to bacterial membranes. These results suggest that 64 Cu-labeled AB1-HLys-DOTA peptide could be used as an imaging probe for detection of bacterial infection in vivo with specificity for Gram-positive bacteria., Competing Interests: The authors do not have any conflicts of interest to declare., (Copyright © 2019 Tolulope A. Aweda et al.)

Background: The success of human epidermal growth factor receptor 2 (HER2)-targeted therapy depends on accurate characterization of HER2 expression, but current methods available have several limitations. This study aims to investigate the feasibility of [ 89 Zr]pertuzumab imaging to monitor early response to Ado-trastuzumab emtansine (T-DM1) therapy in mice bearing xenografts of HER2-positive breast cancer (BCa). Materials and Methods: Pertuzumab was conjugated to DFO-Bz-NCS and labeled with 89 Zr. Mice bearing BT-474 tumors were imaged with [ 89 Zr]pertuzumab and [ 18 F]FDG before and after T-DM1 therapy. Results: Pertuzumab was successfully labeled with 89 Zr with a specific activity of 0.740 MBq/μg. Overall [ 18 F]FDG images showed poor delineation of tumors. Using [ 18 F]FDG-PET to measure tumor volume, the volume remained unchanged from 107.6 ± 20.7 mm 3 before treatment to 89.87 ± 66.55 mm 3 after treatment. In contrast, [ 89 Zr]pertuzumab images showed good delineation of HER2-positive tumors, allowing accurate detection of changes in tumor volume (from 243.80 ± 40.91 mm 3 before treatment to 78.4 ± 40.43 mm 3 after treatment). Conclusion: [ 89 Zr]pertuzumab may be an imaging probe for monitoring the response of HER2-positive BCa patients to T-DM1 therapy.

An increasing interest in zirconium-89 ( 89 Zr) can be attributed to the isotope's half-life which is compatible with antibody imaging using positron emission tomography (PET). The goal of this work was to develop an efficient means of production for 89 Zr that provides this isotope with high radionuclidic purity and specific activity. We investigated the irradiation of yttrium sputtered niobium coins and compared the yields and separation efficiency to solid yttrium coins. The sputtered coins were irradiated with an incident beam energy of 17.5MeV or 17.8MeV providing a degraded transmitted energy through an aluminum degrader of 12.5MeV or 12.8MeV, respectively, with various currents to determine optimal cyclotron conditions for 89 Zr production. Dissolution of the solid yttrium coin took 2h with 50mL of 2M HCl and dissolution of the sputtered coin took 15-30min with 4mL of 2M HCl. During the separation of 89 Zr from the solid yttrium coins, 77.9 ± 11.2% of the activity was eluted off in an average of 7.3mL of 1M oxalic acid whereas for the sputtered coins, 91 ± 6% was eluted off in an average of 1.2mL of 1M oxalic acid with 100% radionuclidic purity. The effective specific activity determined via DFO-SCN titration from the sputtered coins was 108±7mCi/μmol as compared to 20.3mCi/μmol for the solid yttrium coin production. ICP-MS analysis of the yttrium coin and the sputtered coins showed 99.99% yttrium removed with 178μg of yttrium in the final solution and 99.93-100% of yttrium removed with remaining range of 0-42μg of yttrium in the final solution, respectively. The specific activity calculated for the solid coin and 3 different sputtered coins using the concentration of Zr found via ICP-MS was 140±2mCi/μmol, 300±30mCi/μmol, 410±60mCi/μmol and 1719±5mCi/μmol, respectively. Labeling yields of the 89 Zr produced via sputtered targets for 89 Zr- DFO-trastuzumab were >98%. Overall, these results show the irradiation of yttrium sputtered niobium coins is a highly effective means for the production of 89 Zr., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Manganese is essential to life, and humans typically absorb sufficient quantities of this element from a normal healthy diet; however, chronic, elevated ingestion or inhalation of manganese can be neurotoxic, potentially leading to manganism. Although imaging of large amounts of accumulated Mn(II) is possible by MRI, quantitative measurement of the biodistribution of manganese, particularly at the trace level, can be challenging. In this study, we produced the positron-emitting radionuclide 52Mn (t1/2 = 5.6 d) by proton bombardment (Ep<15 MeV) of chromium metal, followed by solid-phase isolation by cation-exchange chromatography. An aqueous solution of [52Mn]MnCl2 was nebulized into a closed chamber with openings through which mice inhaled the aerosol, and a separate cohort of mice received intravenous (IV) injections of [52Mn]MnCl2. Ex vivo biodistribution was performed at 1 h and 1 d post-injection/inhalation (p.i.). In both trials, we observed uptake in lungs and thyroid at 1 d p.i. Manganese is known to cross the blood-brain barrier, as confirmed in our studies following IV injection (0.86%ID/g, 1 d p.i.) and following inhalation of aerosol, (0.31%ID/g, 1 d p.i.). Uptake in salivary gland and pancreas were observed at 1 d p.i. (0.5 and 0.8%ID/g), but to a much greater degree from IV injection (6.8 and 10%ID/g). In a separate study, mice received IV injection of an imaging dose of [52Mn]MnCl2, followed by in vivo imaging by positron emission tomography (PET) and ex vivo biodistribution. The results from this study supported many of the results from the biodistribution-only studies. In this work, we have confirmed results in the literature and contributed new results for the biodistribution of inhaled radiomanganese for several organs. Our results could serve as supporting information for environmental and occupational regulations, for designing PET studies utilizing 52Mn, and/or for predicting the biodistribution of manganese-based MR contrast agents.

Purified (111) Ag was used as a radiotracer to investigate silver loading and release, pharmacokinetics, and biodistribution of polyphosphoester-based degradable shell crosslinked knedel-like (SCK) nanoparticles as a comparison to the previously reported small molecule, N-heterocyclic silver carbene complex analog (SCC1) for the delivery of therapeutic silver ions in mouse models. Biodistribution studies were conducted by aerosol administration of (111) Ag acetate, [(111) Ag]SCC1, and [(111) Ag]SCK doses directly into the lungs of C57BL/6 mice. Nebulization of the (111) Ag antimicrobials resulted in an average uptake of 1.07 ± 0.12% of the total aerosolized dose given per mouse. The average dose taken into the lungs of mice was estimated to be 2.6 ± 0.3% of the dose inhaled per mouse for [(111) Ag]SCC1 and twice as much dose was observed for the [(111) Ag]SCKs (5.0 ± 0.3% and 5.9 ± 0.8% for [(111) Ag]aSCK and [(111) Ag]zSCK, respectively) at 1 h post administration (p.a.). [(111) Ag]SCKs also exhibited higher dose retention in the lungs; 62-68% for [(111) Ag]SCKs and 43% for [(111) Ag]SCC1 of the initial 1 h dose were observed in the lungs at 24 h p.a.. This study demonstrates the utility of (111) Ag as a useful tool for monitoring the pharmacokinetics of silver-loaded antimicrobials in vivo., (Copyright © 2015 John Wiley & Sons, Ltd.)