Development and Evaluation of Interleukin-2–Derived Radiotracers for PET Imaging of T Cells in Mice

Veen, Elly L. van der; Suurs, Frans V.; Cleeren, Frederik; Bormans, Guy; Elsinga, Philip H.; Hospers, Geke A.P.; Hooge, Marjolijn N. Lub-de; Vries, Elisabeth G.E. de; Vries, E. F. J. de; Antunes, Inês Farinha

doi:10.2967/jnumed.119.238782

Cited by 37 publications

(57 citation statements)

References 32 publications

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“…Therefore, more investigations are needed for VCAM-1 nanobody radiotracers to detect such lesions. In order to increase spatial resolution and sensitivity using the latest β-CUBE PET technology, Bridoux et al conjugated cAbVCAM1-5 with a novel restrained complexing agent (RESCA) allowing faster 18 F-labelling via the Al 18 F-method, a process that has already had good results in a previous study concerning the targeting of T-cells by interleukin-2-derived radiotracers [121]. [ 18 F]AlF(RESCA)-cAbVCAM1-5 accumulated in atherosclerotic lesions in the aortic arch of ApoE −/− mice, but also unfortunately in the bone structure, which is probably due to the uptake of degradation products of the tracer by unclear biological processes ( Figure 6).…”

Section: Imaging Of Vcam-1mentioning

confidence: 99%

VCAM-1 Target in Non-Invasive Imaging for the Detection of Atherosclerotic Plaques

Thayse

Kindt

Laurent

et al. 2020

Biology

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Atherosclerosis is a progressive chronic arterial disease characterised by atheromatous plaque formation in the intima of the arterial wall. Several invasive and non-invasive imaging techniques have been developed to detect and characterise atherosclerosis in the vessel wall: anatomic/structural imaging, functional imaging and molecular imaging. In molecular imaging, vascular cell adhesion molecule-1 (VCAM-1) is a promising target for the non-invasive detection of atherosclerosis and for the assessment of novel antiatherogenic treatments. VCAM-1 is an adhesion molecule expressed on the activated endothelial surface that binds leucocyte ligands and therefore promotes leucocyte adhesion and transendothelial migration. Hence, for several years, there has been an increase in molecular imaging methods for detecting VCAM-1 in MRI, PET, SPECT, optical imaging and ultrasound. The use of microparticles of iron oxide (MPIO), ultrasmall superparamagnetic iron oxide (USPIO), microbubbles, echogenic immunoliposomes, peptides, nanobodies and other nanoparticles has been described. However, these approaches have been tested in animal models, and the remaining challenge is bench-to-bedside development and clinical applicability.

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Section: Imaging Of Vcam-1mentioning

confidence: 99%

VCAM-1 Target in Non-Invasive Imaging for the Detection of Atherosclerotic Plaques

Thayse

Kindt

Laurent

et al. 2020

Biology

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“…In our experience, [ 18 F]SFB in DMSO showed better hydrolytic stability, higher reactivity and better solubility than polar protic solvent, ethanol. In addition, the minimal reaction volume (300 µL) with the use of 1 mL V-vial and stirring the contents at 100 rotations per minute (rpm) provided higher RCYs than existing procedures [ 6 , 7 ].…”

Section: Discussionmentioning

confidence: 99%

“…The use of SEC-PD10 column purification and elution buffer 0.05% sodium dodecyl sulphate (SDS) in phosphate-buffered saline (PBS) allowed us to streamline the purification and reformulation of the labelled product for injection into animals. [ 18 F]FB-IL-2 was prepared with 3.8 times higher RCYs and 30 min less reaction time than published articles procedures (1.0 ± 0.4% in 150 min) [ 6 , 7 ].…”

Section: Discussionmentioning

confidence: 99%

“…Several radiopharmaceuticals for PET imaging of IL-2Rs on activated T-cells have already been developed [ 5 , 6 , 7 , 8 ]. Perhaps the most well-characterized of these is N -(4-[ 18 F]fluorobenzoyl)-interleukin-2 ([ 18 F]FB-IL-2), which was developed as a tool for the in vivo identification and quantification of CD25+ T-cells and is currently being evaluated in clinical trials (NCT02922283 and NCT03304223) [ 5 , 6 , 7 , 9 , 10 ]. However, due to a complex production process and low radiochemical yields (RCYs) from protein conjugation reactions, the [ 18 F]FB-IL-2 synthesis requires a high initial amount of radioactivity to provide a suitable quantity of formulated [ 18 F]FB-IL-2 radiopharmaceutical for either clinical or preclinical use [ 6 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

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An Improved Synthesis of N-(4-[18F]Fluorobenzoyl)-Interleukin-2 for the Preclinical PET Imaging of Tumour-Infiltrating T-cells in CT26 and MC38 Colon Cancer Models

et al. 2021

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Positron emission tomography (PET) imaging of activated T-cells with N-(4-[18F]fluorobenzoyl)-interleukin-2 ([18F]FB-IL-2) may be a promising tool for patient management to aid in the assessment of clinical responses to immune therapeutics. Unfortunately, existing radiosynthetic methods are very low yielding due to complex and time-consuming chemical processes. Herein, we report an improved method for the synthesis of [18F]FB-IL-2, which reduces synthesis time and improves radiochemical yield. With this optimized approach, [18F]FB-IL-2 was prepared with a non-decay-corrected radiochemical yield of 3.8 ± 0.7% from [18F]fluoride, 3.8 times higher than previously reported methods. In vitro experiments showed that the radiotracer was stable with good radiochemical purity (>95%), confirmed its identity and showed preferential binding to activated mouse peripheral blood mononuclear cells. Dynamic PET imaging and ex vivo biodistribution studies in naïve Balb/c mice showed organ distribution and kinetics comparable to earlier published data on [18F]FB-IL-2. Significant improvements in the radiochemical manufacture of [18F]FB-IL-2 facilitates access to this promising PET imaging radiopharmaceutical, which may, in turn, provide useful insights into different tumour phenotypes and a greater understanding of the cellular nature and differential immune microenvironments that are critical to understand and develop new treatments for cancers.

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“…This results in the release of [ 18 F]AlF or [ 18 F]F − that returns into blood circulation and accumulates in the bone structures. As this instability appears to be lower in the case of other proteins [20,27], it would be interesting to further investigate the reasons behind the degradation in the case of Nbs.…”

Section: Discussionmentioning

confidence: 99%

Improved Detection of Molecular Markers of Atherosclerotic Plaques Using Sub-Millimeter PET Imaging

Bridoux

Neyt²,

Debie

et al. 2020

Molecules

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Since atherosclerotic plaques are small and sparse, their non-invasive detection via PET imaging requires both highly specific radiotracers as well as imaging systems with high sensitivity and resolution. This study aimed to assess the targeting and biodistribution of a novel fluorine-18 anti-VCAM-1 Nanobody (Nb), and to investigate whether sub-millimetre resolution PET imaging could improve detectability of plaques in mice. The anti-VCAM-1 Nb functionalised with the novel restrained complexing agent (RESCA) chelator was labelled with [18F]AlF with a high radiochemical yield (>75%) and radiochemical purity (>99%). Subsequently, [18F]AlF(RESCA)-cAbVCAM1-5 was injected in ApoE−/− mice, or co-injected with excess of unlabelled Nb (control group). Mice were imaged sequentially using a cross-over design on two different commercially available PET/CT systems and finally sacrificed for ex vivo analysis. Both the PET/CT images and ex vivo data showed specific uptake of [18F]AlF(RESCA)-cAbVCAM1-5 in atherosclerotic lesions. Non-specific bone uptake was also noticeable, most probably due to in vivo defluorination. Image analysis yielded higher target-to-heart and target-to-brain ratios with the β-CUBE (MOLECUBES) PET scanner, demonstrating that preclinical detection of atherosclerotic lesions could be improved using the latest PET technology.

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Development and Evaluation of Interleukin-2–Derived Radiotracers for PET Imaging of T Cells in Mice

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Cited by 37 publications

References 32 publications

VCAM-1 Target in Non-Invasive Imaging for the Detection of Atherosclerotic Plaques

VCAM-1 Target in Non-Invasive Imaging for the Detection of Atherosclerotic Plaques

An Improved Synthesis of N-(4-[18F]Fluorobenzoyl)-Interleukin-2 for the Preclinical PET Imaging of Tumour-Infiltrating T-cells in CT26 and MC38 Colon Cancer Models

Improved Detection of Molecular Markers of Atherosclerotic Plaques Using Sub-Millimeter PET Imaging

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