Dataset Information

Preliminary Characterization and In Vivo Studies of Structurally Identical (18)F- and (125)I-Labeled Benzyloxybenzenes for PET/SPECT Imaging of ?-Amyloid Plaques.

ABSTRACT: With the assistance of molecular docking and 3D-QSAR models established previously, structurally identical (18)F- and (125)I-labeled benzyloxybenzene derivatives were designed to achieve the early detection of A? plaques by PET/SPECT imaging. In competition binding assay, ligands 7a and 12a displayed high binding affinities to A?42 aggregates with Ki values of 19.5?nM and 23.9?nM, respectively. Specific plaque labeling was observed on the in vitro autoradiography of brain sections from AD patients and Tg mice. In biodistribution, [(125)I]7a, [(18)F]7a, [(125)I]12a and [(18)F]12a all exhibited high initial brain uptakes (>5% ID/g at 2?min). [(125)I]7a and [(125)I]12a cleared fast from the normal brain regions, while corresponding [(18)F]7a and [(18)F]12a showed slow washout rates. Dynamic microPET/CT and microSPECT/CT imaging data in normal ICR mice were in accordance with in vivo biodistribution results. In vivo metabolism results indicated that the different clearance profiles between the structurally identical (18)F- and (125)I-labeled tracers could be attributed to different biochemical characteristics of the radiometabolites. Radioiodinated benzyloxybenzene derivatives exhibited good in vivo biostability in brain. Ex vivo autoradiography further confirmed the strong in vivo A? labeling ability of [(125)I]7a. These new fluorinated and iodinated benzyloxybenzenes can develop into PET/SPECT dual imaging agents targeting A? plaques.

SUBMITTER: Yang Y

PROVIDER: S-EPMC4501006 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Preliminary Characterization and In Vivo Studies of Structurally Identical (18)F- and (125)I-Labeled Benzyloxybenzenes for PET/SPECT Imaging of β-Amyloid Plaques.

Yang Yanping Y Zhang Xiaoyang X Cui Mengchao M Zhang Jinming J Guo Zhide Z Li Yesen Y Zhang Xianzhong X Dai Jiapei J Liu Boli B

Scientific reports 20150714

With the assistance of molecular docking and 3D-QSAR models established previously, structurally identical (18)F- and (125)I-labeled benzyloxybenzene derivatives were designed to achieve the early detection of Aβ plaques by PET/SPECT imaging. In competition binding assay, ligands 7a and 12a displayed high binding affinities to Aβ42 aggregates with Ki values of 19.5 nM and 23.9 nM, respectively. Specific plaque labeling was observed on the in vitro autoradiography of brain sections from AD patien ...[more]

PMID: 26170205

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Project description:Background: The pretargeted imaging strategy using inverse electron demand Diels-Alder (IEDDA) cycloaddition between a trans-cyclooctene (TCO) and tetrazine (Tz) has emerged and rapidly grown as a promising concept to improve radionuclide imaging and therapy in oncology. This strategy has mostly relied on the use of radiolabeled Tz together with TCO-modified targeting vectors leading to a rapid growth of the number of available radiolabeled tetrazines, while only a few radiolabeled TCOs are currently reported. Here, we aim to develop novel and structurally diverse 18F-labeled cis-dioxolane-fused TCO (d-TCO) derivatives to further expand the bioorthogonal toolbox for in vivo ligation and evaluate their potential for positron emission tomography (PET) pretargeted imaging. Results: A small series of d-TCO derivatives were synthesized and tested for their reactivity against tetrazines, with all compounds showing fast reaction kinetics with tetrazines. A fluorescence-based pretargeted blocking study was developed to investigate the in vivo ligation of these compounds without labor-intensive prior radiochemical development. Two compounds showed excellent in vivo ligation results with blocking efficiencies of 95 and 97%. Two novel 18F-labeled d-TCO radiotracers were developed, from which [18F]MICA-214 showed good in vitro stability, favorable pharmacokinetics, and moderate in vivo stability. Micro-PET pretargeted imaging with [18F]MICA-214 in mice bearing LS174T tumors treated with tetrazine-modified CC49 monoclonal antibody (mAb) (CC49-Tz) showed significantly higher uptake in tumor tissue in the pretargeted group (CC49-Tz 2.16 ± 0.08% ID/mL) when compared to the control group with nonmodified mAb (CC49 1.34 ± 0.07% ID/mL). Conclusions: A diverse series of fast-reacting fluorinated d-TCOs were synthesized. A pretargeted blocking approach in tumor-bearing mice allowed the choice of a lead compound with fast reaction kinetics with Tz. A novel 18F-labeled d-TCO tracer was developed and used in a pretargeted PET imaging approach, allowing specific tumor visualization in a mouse model of colorectal cancer. Although further optimization of the radiotracer is needed to enhance the tumor-to-background ratios for pretargeted imaging, we anticipate that the 18F-labeled d-TCO will find use in studies where increased hydrophilicity and fast bioconjugation are required.

Project description:BackgroundCardiac PET has recently found novel applications in coronary atherosclerosis imaging using [18F]NaF as a radiotracer, highlighting vulnerable plaques. However, the resulting uptakes are relatively small, and cardiac motion and respiration-induced movement of the heart can impair the reconstructed images due to motion blurring and attenuation correction mismatches. This study aimed to apply an MR-based motion compensation framework to [18F]NaF data yielding high-resolution motion-compensated PET and MR images.MethodsFree-breathing 3-dimensional Dixon MR data were acquired, retrospectively binned into multiple respiratory and cardiac motion states, and split into fat and water fraction using a model-based reconstruction framework. From the dynamic MR reconstructions, both a non-rigid cardiorespiratory motion model and a motion-resolved attenuation map were generated and applied to the PET data to improve image quality. The approach was tested in 10 patients and focal tracer hotspots were evaluated concerning their target-to-background ratio, contrast-to-background ratio, and their diameter.ResultsMR-based motion models were successfully applied to compensate for physiological motion in both PET and MR. Target-to-background ratios of identified plaques improved by 7 ± 7%, contrast-to-background ratios by 26 ± 38%, and the plaque diameter decreased by -22 ± 18%. MR-based dynamic attenuation correction strongly reduced attenuation correction artefacts and was not affected by stent-related signal voids in the underlying MR reconstructions.ConclusionsThe MR-based motion correction framework presented here can improve the target-to-background, contrast-to-background, and width of focal tracer hotspots in the coronary system. The dynamic attenuation correction could effectively mitigate the risk of attenuation correction artefacts in the coronaries at the lung-soft tissue boundary. In combination, this could enable a more reproducible and reliable plaque localisation.

Dataset Information

Preliminary Characterization and In Vivo Studies of Structurally Identical (18)F- and (125)I-Labeled Benzyloxybenzenes for PET/SPECT Imaging of ?-Amyloid Plaques.

Publications

Preliminary Characterization and In Vivo Studies of Structurally Identical (18)F- and (125)I-Labeled Benzyloxybenzenes for PET/SPECT Imaging of β-Amyloid Plaques.

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