Dataset Information

Preclinical properties and human in vivo assessment of 123I-ABC577 as a novel SPECT agent for imaging amyloid-?.

ABSTRACT: Non-invasive imaging of amyloid-? in the brain, a hallmark of Alzheimer's disease, may support earlier and more accurate diagnosis of the disease. In this study, we assessed the novel single photon emission computed tomography tracer (123)I-ABC577 as a potential imaging biomarker for amyloid-? in the brain. The radio-iodinated imidazopyridine derivative (123)I-ABC577 was designed as a candidate for a novel amyloid-? imaging agent. The binding affinity of (123)I-ABC577 for amyloid-? was evaluated by saturation binding assay and in vitro autoradiography using post-mortem Alzheimer's disease brain tissue. Biodistribution experiments using normal rats were performed to evaluate the biokinetics of (123)I-ABC577. Furthermore, to validate (123)I-ABC577 as a biomarker for Alzheimer's disease, we performed a clinical study to compare the brain uptake of (123)I-ABC577 in three patients with Alzheimer's disease and three healthy control subjects. (123)I-ABC577 binding was quantified by use of the standardized uptake value ratio, which was calculated for the cortex using the cerebellum as a reference region. Standardized uptake value ratio images were visually scored as positive or negative. As a result, (123)I-ABC577 showed high binding affinity for amyloid-? and desirable pharmacokinetics in the preclinical studies. In the clinical study, (123)I-ABC577 was an effective marker for discriminating patients with Alzheimer's disease from healthy control subjects based on visual images or the ratio of cortical-to-cerebellar binding. In patients with Alzheimer's disease, (123)I-ABC577 demonstrated clear retention in cortical regions known to accumulate amyloid, such as the frontal cortex, temporal cortex, and posterior cingulate. In contrast, less, more diffuse, and non-specific uptake without localization to these key regions was observed in healthy controls. At 150 min after injection, the cortical standardized uptake value ratio increased by ? 60% in patients with Alzheimer's disease relative to healthy control subjects. Both healthy control subjects and patients with Alzheimer's disease showed minimal (123)I-ABC577 retention in the white matter. These observations indicate that (123)I-ABC577 may be a useful single photon emission computed tomography imaging maker to identify amyloid-? in the human brain. The availability of an amyloid-? tracer for single photon emission computed tomography might increase the accessibility of diagnostic imaging for Alzheimer's disease.

SUBMITTER: Maya Y

PROVIDER: S-EPMC4949387 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Preclinical properties and human in vivo assessment of 123I-ABC577 as a novel SPECT agent for imaging amyloid-β.

Maya Yoshifumi Y Okumura Yuki Y Kobayashi Ryohei R Onishi Takako T Shoyama Yoshinari Y Barret Olivier O Alagille David D Jennings Danna D Marek Kenneth K Seibyl John J Tamagnan Gilles G Tanaka Akihiro A Shirakami Yoshifumi Y

Brain : a journal of neurology 20151021 Pt 1

Non-invasive imaging of amyloid-β in the brain, a hallmark of Alzheimer's disease, may support earlier and more accurate diagnosis of the disease. In this study, we assessed the novel single photon emission computed tomography tracer (123)I-ABC577 as a potential imaging biomarker for amyloid-β in the brain. The radio-iodinated imidazopyridine derivative (123)I-ABC577 was designed as a candidate for a novel amyloid-β imaging agent. The binding affinity of (123)I-ABC577 for amyloid-β was evaluated ...[more]

PMID: 26490333

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Project description:BACKGROUND:[123I]epidepride is a high-affinity radiotracer used in single-photon emission computed tomography (SPECT) imaging of the D2/3 receptors. It binds with high affinity to striatal and extrastriatal receptors. Nevertheless, its slow kinetics in the striatum impedes quantification in this region. Thus, an approach that would allow a simultaneous quantification of both striatal and extrastriatal D2/3 receptors would be of interest for preclinical and clinical SPECT neuroimaging. We describe a partial saturation protocol that allows us to produce an in vivo Scatchard plot and thus estimate Bavail and appKd separately in both striatal and extrastriatal regions, through a single dynamic SPECT session. To validate this approach, a multi-injection protocol is used for the full kinetic modeling of [123I]epidepride using a two-tissue compartment, 5-parameter model (2T-5k). METHODS:Eighteen male rats were used. Binding parameters were estimated using the multi-injection protocol. Various simulations were performed to estimate the optimal conditions for the partial saturation protocol, which was applied at the region and voxel level. The results of the partial saturation study were compared to those obtained with the 2T-5k model. To illustrate the interest of the partial saturation approach, we performed a preliminary study of the effect of a chronic, subcutaneous administration of haloperidol (1?mg/kg/day), a D2 receptor antagonist, on the Bavail of [123I]epidepride in the rat striatum. RESULTS:A series of simulations demonstrated that a mass of 3 ug/kg of unlabeled epidepride allows the formation of an in vivo Scatchard plot. The partial saturation study led to robust estimations of Bavail in all brain regions that highly correlated (r = 0.99) with the corresponding values from the multi-injection study. A chronic haloperidol treatment resulted in a 17.9% increase in the Bavail values in the left Caudate Putamen nucleus (CP) (p = 0.07) and a 13.8% increase in the right CP (p = 0.12). CONCLUSION:A partial saturation method allowed the robust quantification of D2/3 receptors in striatal and extrastriatal D2/3 receptors with a single-scan approach. This approach may be applied in the mapping of the D2/3 receptor in translational biological studies and potentially, in clinical SPECT imaging.

Project description:Authors' goal is to evaluate the performance of simultaneous (99m)Tc-MDP/(123)I-MIBG tumor imaging with fast Monte-Carlo (MC) based joint iterative reconstruction as compared to sequential (99m)Tc-MDP and (123)I-MIBG tumor imaging.Noise-free (99m)Tc and (123)I SPECT projections were acquired separately using an anthropomorphic torso phantom modified to include a fillable tube around the lungs to mimic ribs. Additionally, (99m)Tc and (123)I projections were acquired separately using a 1-cm spherical "tumor" placed at various distances from one detector. Tumor-present data were generated by adding tumor projections to the torso phantom data, which were scaled to the total counts in typical clinical studies. Twenty-five noise realizations were generated by adding Poisson noise to the projection data for each radionuclide. Dual-radionuclide data were synthesized by summing the (99m)Tc and (123)I projections. Image reconstruction was performed using: (1) SR-OSEM, ordered subset expectation maximization (OSEM) without scatter correction (SC) using single-radionuclide (SR) data; (2) SR-MC-OSEM, OSEM with a fast MC-based SC using SR data; (3) DR-OSEM, OSEM without SC using dual-radionuclide (DR) data; and (4) DR-MC-JOSEM, joint OSEM with a fast MC-based SC using DR data. Ten (99m)Tc-MDP and ten (123)I-MIBG data sets, which had tumors mathematically inserted, were also used to evaluate the performance of authors' approach. For the phantom study, relative bias and relative standard deviation of tumor uptake were computed for each tumor using the tumor uptake in the noise-free single-radionuclide images, which were reconstructed by SR-MC-OSEM, as the gold standard. For both the phantom and constructed patient studies, mean contrast and standard deviation of contrast were computed for each tumor for both the single- and dual-radionuclide images. Additionally, contrast recovery was computed as the ratio between mean contrast and the mean contrast for SR-MC-OSEM.For the phantom study, DR-MC-JOSEM yielded 2.7% on average relative bias of tumor uptake using the images, which were reconstructed from the noise-free SR data with SR-MC-OSEM, as the gold-standard. For both the phantom and constructed patient studies, DR-MC-JOSEM yielded 94.7% and 95.2% tumor contrast recovery on average using SR-MC-OSEM as the reference, in the phantom and constructed patient studies, respectively. DR-MC-JOSEM yielded comparable relative standard deviation of bias and standard deviation of contrast to SR-MC-OSEM.Simultaneous (99m)Tc-MDP/(123)I-MIBG tumor imaging using authors' dual-radionuclide reconstruction approach yielded comparable image quality to sequential (99m)Tc-MDP and (123)I-MIBG imaging. For patients who need to undergo both scans, authors' approach offers perfectly registered dual-tracer images under identical conditions without compromising image quality, and reduces the imaging cost while increasing patient throughput.

Project description:BACKGROUND:Currently, there is no established non-invasive imaging approach to directly evaluate myocardial microcirculatory function in order to diagnose microvascular disease independent of co-existing epicardial disease. In this work, we developed a methodological framework for quantification of intramyocardial blood volume (IMBV) as a novel index of microcirculatory function with SPECT/CT imaging of 99mTc-labeled red blood cells (RBCs). METHODS:Dual-gated myocardial SPECT/CT equilibrium imaging of 99mTc-RBCs was performed on twelve canines under resting conditions. Five correction schemes were studied: cardiac gating with no other corrections (CG), CG with attenuation correction (CG + AC), CG + AC with scatter correction (CG + AC + SC), dual cardiorespiratory gating with AC + SC (DG + AC + SC), and DG + AC + SC with partial volume correction (DG + AC + SC + PVC). Quantification of IMBV using each approach was evaluated in comparison to those obtained from all corrections. The in vivo SPECT estimates of IMBV values were validated against those obtained from ex vivo microCT imaging of the casted hearts. RESULTS:The estimated IMBV with all corrections was 0.15 ± 0.03 for the end-diastolic phase and 0.11 ± 0.03 for the end-systolic phase. The cycle-dependent change in IMBV (?IMBV) with all corrections was 23.9 ± 8.6%. Schemes that applied no correction or partial correction resulted in significant over-estimation of IMBV and significant under-underestimation of ?IMBV. Estimates of IMBV and ?IMBV using all corrections were consistent with values reported in the literature using invasive techniques. In vivo SPECT estimates of IMBV strongly correlated (R2 ? 0.70) with ex vivo measures for the various correction schemes, while the fully corrected scheme yielded the smallest bias. CONCLUSIONS:Non-invasive quantification of IMBV is feasible using 99mTc-RBCs SPECT/CT imaging, however, requires full compensation of physical degradation factors.

Dataset Information

Preclinical properties and human in vivo assessment of 123I-ABC577 as a novel SPECT agent for imaging amyloid-?.

Publications

Preclinical properties and human in vivo assessment of 123I-ABC577 as a novel SPECT agent for imaging amyloid-β.

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