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Introduction: Nuclear medicine infection imaging is routinely performed with the use of leukocytes radiolabelled with technetium-99m hexamethylpropyleneamine oxime ([99mTc]Tc-HMPAO) and single-photon emission computed tomography (SPECT). Positron emission tomography (PET) is more sensitive than SPECT and results in higher-quality images. Zirconium-89 (89Zr) is a positron emitter with a half-life of 78.4 h, which translates to the biological half-life and slow biodistribution of intact cells and allows delayed PET imaging for more accurate biodistribution of the labelled leukocytes to infection foci. A first-in-human study with [89Zr]Zr-oxine-leukocytes in four healthy volunteers was reported in 2022. Our first-in-human study utilising the cell surface labelling approach aimed to image infection in patients with the use of 89Zr-labelled leukocytes, using p-isothiocyanatobenzyl-desferrioxamine B (Df-Bz-NCS) as a bifunctional chelating agent, and to compare the scan quality and biodistribution of [89Zr]Zr-Df-Bz-NCS-labelled leukocytes on PET images to SPECT images obtained with [99mTc]Tc-HMPAO-labelled leukocytes. Methods: Leukocytes were isolated from whole-blood samples of eight patients with clinically and/or radiologically confirmed infection. Isolated leukocytes were labelled with [99mTc]Tc-HMPAO according to standardised methods, and [89Zr]Zr-Df-Bz-NCS according to our previously published radiolabelling method. Whole-body SPECT imaging was performed 2 and 18 h post injection of [99mTc]Tc-HMPAO-labelled leukocytes, and whole-body PET/CT was performed 3 and 24 h post injection of [89Zr]Zr-Df-Bz-NCS-labelled leukocytes in seven patients. Results: Successful [89Zr]Zr-Df-Bz-NCS-leukocyte labelling was achieved. High labelling efficiencies were obtained (81.7% ± 3.6%; n = 8). A mean high viability of [89Zr]Zr-Df-Bz-NCS-labelled leukocytes was observed (88.98% ± 12.51%). The [89Zr]Zr-Df-Bz-NCS-leukocyte labelling efficiency was not significantly affected by the white blood cell count of the patient. The performance of [99mTc]Tc-HMPAOand [89Zr]Zr-Df-Bz-NCS-labelled leukocytes, in terms of the ability to accurately detect infection, were similar in two out of seven patients, and [99mTc]Tc-HMPAOlabelled leukocytes outperformed [89Zr]Zr-Df-Bz-NCS-labelled leukocytes in one patient with femoral osteomyelitis. However, in two cases of pulmonary pathology, [89Zr]Zr-Df-Bz-NCS-labelled leukocytes demonstrated improved pathological uptake. No skeletal activity was observed in any of the patients imaged with [89Zr] Zr-Df-Bz-NCS-labelled leukocytes, illustrating the in vivo stability of the radiolabel. Discussion: Although the [89Zr]Zr-Df-Bz-NCS-leukocyte labelling aspect of this study was noteworthy, infection imaging did not yield convincingly positive results due to the pulmonary trapping of intravenously administered [89Zr]Zr-Df-Bz-NCS-labelled leukocytes. [ABSTRACT FROM AUTHOR]

Background: The non-invasive imaging of leukocyte trafficking to assess inflammatory areas and monitor immunotherapy is currently generating great interest. There is a need to develop more robust cell labelling and imaging approaches to track living cells. Positron emission tomography (PET), a highly sensitive molecular imaging technique, allows precise signals to be produced from radiolabelled moieties. Here, we developed a novel leukocyte labelling approach with the PET radioisotope zirconium-89 (89Zr, half-life of 78.4 h). Experiments were carried out using human leukocytes, freshly isolated from whole human blood. Results: The 89Zr-leukocyte labelling efficiency ranged from 46 to 87% after 30–60 min. Radioactivity concentrations of labelled cells were up to 0.28 MBq/1 million cells. Systemically administered 89Zr-labelled leukocytes produced high-contrast murine PET images at 1 h–5 days post injection. Murine biodistribution data showed that cells primarily distributed to the lung, liver, and spleen at 1 h post injection, and are then gradually trafficked to liver and spleen over 5 days. Histological analysis demonstrated that exogenously 89Zr-labelled human leukocytes were present in the lung, liver, and spleen at 1 h post injection. However, intravenously injected free [89Zr]Zr4+ ion showed retention only in the bone with no radioactivity in the lung at 5 days post injection, which implied good stability of radiolabelled leukocytes in vivo. Conclusions: Our study presents a stable and generic radiolabelling technique to track leukocytes with PET imaging and shows great potential for further applications in inflammatory cell and other types of cell trafficking studies. [ABSTRACT FROM AUTHOR]

Introduction: Nuclear medicine infection imaging is routinely performed with the use of leukocytes radiolabelled with technetium-99m hexamethylpropyleneamine oxime ([ 99m Tc]Tc-HMPAO) and single-photon emission computed tomography (SPECT). Positron emission tomography (PET) is more sensitive than SPECT and results in higher-quality images. Zirconium-89 ( 89 Zr) is a positron emitter with a half-life of 78.4 h, which translates to the biological half-life and slow biodistribution of intact cells and allows delayed PET imaging for more accurate biodistribution of the labelled leukocytes to infection foci. A first-in-human study with [ 89 Zr]Zr-oxine-leukocytes in four healthy volunteers was reported in 2022. Our first-in-human study utilising the cell surface labelling approach aimed to image infection in patients with the use of 89 Zr-labelled leukocytes, using p -isothiocyanatobenzyl-desferrioxamine B (Df-Bz-NCS) as a bifunctional chelating agent, and to compare the scan quality and biodistribution of [ 89 Zr]Zr-Df-Bz-NCS-labelled leukocytes on PET images to SPECT images obtained with [ 99m Tc]Tc-HMPAO-labelled leukocytes., Methods: Leukocytes were isolated from whole-blood samples of eight patients with clinically and/or radiologically confirmed infection. Isolated leukocytes were labelled with [ 99m Tc]Tc-HMPAO according to standardised methods, and [ 89 Zr]Zr-Df-Bz-NCS according to our previously published radiolabelling method. Whole-body SPECT imaging was performed 2 and 18 h post injection of [ 99m Tc]Tc-HMPAO-labelled leukocytes, and whole-body PET/CT was performed 3 and 24 h post injection of [ 89 Zr]Zr-Df-Bz-NCS-labelled leukocytes in seven patients., Results: Successful [ 89 Zr]Zr-Df-Bz-NCS-leukocyte labelling was achieved. High labelling efficiencies were obtained (81.7% ± 3.6%; n  = 8). A mean high viability of [ 89 Zr]Zr-Df-Bz-NCS-labelled leukocytes was observed (88.98% ± 12.51%). The [ 89 Zr]Zr-Df-Bz-NCS-leukocyte labelling efficiency was not significantly affected by the white blood cell count of the patient. The performance of [ 99m Tc]Tc-HMPAO- and [ 89 Zr]Zr-Df-Bz-NCS-labelled leukocytes, in terms of the ability to accurately detect infection, were similar in two out of seven patients, and [ 99m Tc]Tc-HMPAO-labelled leukocytes outperformed [ 89 Zr]Zr-Df-Bz-NCS-labelled leukocytes in one patient with femoral osteomyelitis. However, in two cases of pulmonary pathology, [ 89 Zr]Zr-Df-Bz-NCS-labelled leukocytes demonstrated improved pathological uptake. No skeletal activity was observed in any of the patients imaged with [ 89 Zr]Zr-Df-Bz-NCS-labelled leukocytes, illustrating the in vivo stability of the radiolabel., Discussion: Although the [ 89 Zr]Zr-Df-Bz-NCS-leukocyte labelling aspect of this study was noteworthy, infection imaging did not yield convincingly positive results due to the pulmonary trapping of intravenously administered [ 89 Zr]Zr-Df-Bz-NCS-labelled leukocytes., Competing Interests: TE and JZ were employed by The South African Nuclear Energy Corporation. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (© 2024 Kahts, Summers, Ndlela, Gutta, Nemutaduni, More, Parsoo, Ebenhan, Zeevaart, Aras and Sathekge.)