Synthesis and evaluation of a novel Tc-labeled bioreductive probe for tumor hypoxia imaging

Tumor hypoxia is closely associated with the malignant progression and/or the high metastatic ability of tumors and often induces resistance to chemo- and/or radiotherapy. Thus, the detection and evaluation of hypoxia is important for the optimization of cancer therapy. We designed a novel ^99mTc-labeled probe for tumor hypoxia imaging that utilizes bioreductive reactions in hypoxic cells. This probe, which contains a 4-nitrobenzyl ester group, is reduced in hypoxic cells to produce a corresponding carboxylate anion that cannot penetrate cell membranes because of its hydrophilicity and negative charge; therefore, it is expected to be trapped inside hypoxic cells. Based on this unique strategy, we synthesized the Technetium-99m (^99mTc)-labeled probe ^99mTc-SD32. The uptake of ^99mTc-SD32 in tumor cells was investigated under normoxic and hypoxic conditions. ^99mTc-SD32 showed sufficient accumulation and good retention in hypoxic cells. In addition, we demonstrated that ^99mTc-SD32 was subjected to bioreduction in hypoxic cells and was trapped as the corresponding carboxylate anion. These results indicated that ^99mTc-SD32 would be a promising agent for in vivo hypoxia imaging.     

Prompt gamma ray imaging for verification of proton boron fusion therapy: A Monte Carlo study

PurposeThe purpose of this study was to verify acquisition feasibility of a single photon emission computed tomography image using prompt gamma rays for proton boron fusion therapy (PBFT) and to confirm an enhanced therapeutic effect of PBFT by comparison with conventional proton therapy without use of boron.MethodsMonte Carlo simulation was performed to acquire reconstructed image during PBFT. We acquired percentage depth dose (PDD) of the proton beams in a water phantom, energy spectrum of the prompt gamma rays, and tomographic images, including the boron uptake region (BUR; target). The prompt gamma ray image was reconstructed using maximum likelihood expectation maximisation (MLEM) with 64 projection raw data. To verify the reconstructed image, both an image profile and contrast analysis according to the iteration number were conducted. In addition, the physical distance between two BURs in the region of interest of each BUR was measured.ResultsThe PDD of the proton beam from the water phantom including the BURs shows more efficient than that of conventional proton therapy on tumour region. A 719 keV prompt gamma ray peak was clearly observed in the prompt gamma ray energy spectrum. The prompt gamma ray image was reconstructed successfully using 64 projections. Different image profiles including two BURs were acquired from the reconstructed image according to the iteration number.ConclusionWe confirmed successful acquisition of a prompt gamma ray image during PBFT. In addition, the quantitative image analysis results showed relatively good performance for further study.     

Rhenium and technetium complexes with anionic or neutral scorpionates: An overview of their relevance in biomedical applications

This article reviews the chemistry of Re and Tc complexes anchored by anionic and neutral scorpionates with potential relevance in the field of biomedical applications, particularly in radiopharmaceutical research. For poly(azolyl)borates, the revised work focuses mainly on poly(mercaptoimidazolyl)borate tricarbonyl M(I) complexes, while for tris(pyrazolyl)methanes the revision includes M(VII) trioxo- and M(I) tricarbonyl complexes. A comprehensive update of structural, chemical, radiochemical and biological aspects relevant for the use of these compounds in the design of radiopharmaceuticals is presented and discussed.     

MRI-guided voxel-based automatic semi-quantification of dopamine transporter imaging

PurposeFunctional imaging with ¹²³I-FP-CIT SPECT suffers from poor spatial resolution resulting in partial-volume effect, which affects the subsequent semi-quantification. Definition of regions of interest for semi-quantification is further subject to user's experience and inter-observer variability. The aim of this work has been to develop an automatic method for definition of volumes of interest and partial-volume correction using patient-specific MRI and providing complete contrast recovery in striatal region.MethodThe method consists of spatial pre-processing (image segmentation and multi-modality registration), partial-volume correction (performed by region-based voxel-wise technique), and calculation of uptake indices in striatal structures. Anthropomorphic striatal phantom was used to optimize the method and to assess linearity, accuracy, and reproducibility. The method was tested on 58 patient datasets and compared with clinical assessment and BasGan software.ResultsThe method works automatically. The output is highly linear regarding changing striatal uptake. Complete contrast recovery is achieved using 6.5 mm FWHM. Accuracy is better than 0.15 in terms of RMSE between measured and true uptake indices. Reproducibility is better than 5% for normal uptake ratio. The method outperformed clinical assessment in all measures. With patient data, it provided results closer to BasGan (RMSE 0.9) than to clinical assessment (RMSE 1.9) and fairly correlated with both.ConclusionThe proposed method provides complete recovery of striatal contrast under given acquisition and reconstruction conditions. It reduces intra- and inter-observer variability, accurately defines volumes of interest, and effectively suppresses partial-volume effect. It can be reproduced using publicly available software.     

Partie 3. Infections osseuses (hors greffe sur matériel)

Bone scintigraphy is a nuclear imaging scan using a radiopharmaceutical composed of a bisphosphonate coupled to a radionuclide (technetium 99m). Radiopharmaceutical uptake is particularly important at the level of the bone structures having a strong osteoblastic activity. These uptakes can be due to a benign pathology (fracture, loosening of prosthesis, rheumatic pathologies, etc.) or to a malignant pathology (primary or secondary bone lesion). The high sensitivity of bone scintigraphy makes it particularly interesting at the initial stage of the pathology, especially when X-rays are normal. In addition, its specificity has clearly improved in recent years with the increasingly use of tomoscintigraphy coupled with X-ray scanning (SPECT/CT). We describe the operating principle of bone scintigraphy, normal uptakes with its variants as well as pathological uptake features in traumatic, rheumatic, prosthetic or cancerous pathologies.     

Partie 4. Rhumatologie

Bone scintigraphy is a nuclear imaging scan using a radiopharmaceutical composed of a bisphosphonate coupled to a radionuclide (technetium 99m). Radiopharmaceutical uptake is particularly important at the level of the bone structures having a strong osteoblastic activity. These uptakes can be due to a benign pathology (fracture, loosening of prosthesis, rheumatic pathologies, etc.) or to a malignant pathology (primary or secondary bone lesion). The high sensitivity of bone scintigraphy makes it particularly interesting at the initial stage of the pathology, especially when X-rays are normal. In addition, its specificity has clearly improved in recent years with the increasingly use of tomoscintigraphy coupled with X-ray scanning (SPECT/CT). We describe the operating principle of bone scintigraphy, normal uptakes with its variants as well as pathological uptake features in traumatic, rheumatic, prosthetic or cancerous pathologies.     

Resolution-recovery-embedded image reconstruction for a high-resolution animal SPECT system

The small-animal High-Resolution SPECT (HiReSPECT) is a dedicated dual-head gamma camera recently designed and developed in our laboratory for imaging of murine models. Each detector is composed of an array of 1.2 × 1.2 mm² (pitch) pixelated CsI(Na) crystals. Two position-sensitive photomultiplier tubes (H8500) are coupled to each head's crystal. In this paper, we report on a resolution-recovery-embedded image reconstruction code applicable to the system and present the experimental results achieved using different phantoms and mouse scans. Collimator-detector response functions (CDRFs) were measured via a pixel-driven method using capillary sources at finite distances from the head within the field of view (FOV). CDRFs were then fitted by independent Gaussian functions. Thereafter, linear interpolations were applied to the standard deviation (σ) values of the fitted Gaussians, yielding a continuous map of CDRF at varying distances from the head. A rotation-based maximum-likelihood expectation maximization (MLEM) method was used for reconstruction. A fast rotation algorithm was developed to rotate the image matrix according to the desired angle by means of pre-generated rotation maps. The experiments demonstrated improved resolution utilizing our resolution-recovery-embedded image reconstruction. While the full-width at half-maximum (FWHM) radial and tangential resolution measurements of the system were over 2 mm in nearly all positions within the FOV without resolution recovery, reaching around 2.5 mm in some locations, they fell below 1.8 mm everywhere within the FOV using the resolution-recovery algorithm. The noise performance of the system was also acceptable; the standard deviation of the average counts per voxel in the reconstructed images was 6.6% and 8.3% without and with resolution recovery, respectively.     

Functionalized thymidine derivatives as carriers for the γ-emitter technetium tricarbonyl moiety

Nuclear medicine imaging of cell proliferation has gained broad interest in clinical oncology. A good tracer to image cell proliferation, possibly associated to tumour progression, should rapidly and specifically be incorporated into growing DNA. Following this idea, we have singled out thymidine as a potential biological carrier for delivery of the organometallic fragment [M(CO)₃]⁺ (M = “cold” Re, γ-emitter ^99mTc) to DNA. In the present paper we report the two-step synthesis of thymidine N-3 derivatives and their coordination complexes. Thymidine could be alkylated without protecting the sugar alcoholic functions. Methyl-2,2′-diaminodiethylamine thymidine derivative was quickly reacted with rhenium and technetium carbonyls in almost quantitative yield. The resulting ^99mTc complex represents a convenient radiopharmaceutical for single photon emission tomography (SPECT).     

Small organic probes as amyloid specific ligands - Past and recent molecular scaffolds

Molecular probes for selective staining and imaging of protein aggregates, such as amyloid, are important to advance our understanding of the molecular mechanisms underlying protein misfolding diseases and also for obtaining an early and accurate clinical diagnosis of these disorders. Since normal immunohistochemical reagents, such as antibodies have shown limitation for identifying protein aggregates both in vitro and in vivo, small organic probes have been utilized as amyloid specific markers. In this review, past and recent molecular scaffolds that have been utilized for the development of small organic amyloid imaging agents are discussed.     

A longitudinal follow-up study of the quantification of dopamine transporters with 123I-Ioflupane (DaTscan)

IntroductionThe aim of this study was to test a quantification tool to measure the evolution of the functional reserve of dopaminergic transporters, from two consecutive ¹²³I-Ioflupane Datscan.MethodsImages of 58 patients who underwent two consecutive ¹²³I-Ioflupane examinations (DaTscan^®) in the Nuclear Medicine Department of Toulouse University Hospital from 2002 to 2016 were analysed in this retrospective study. Twenty-four patients had a normal dopaminergic neuronal operation (N group), 34 had a pathological impairment of the dopamine transporters (P group) which 15 did not receive any treatment (PO group) and 16 who received treatment (P1 group). The DaTscan^® image quantification was performed with the DaTsofr3D^® software, permitting to measure the right and left binding potential (PL) of the caudate nucleus (NC), putamen (PU) and striatum (ST).ResultsIn the N group, the annual mean change of the binding potential (NC, PU, ST) was respectively (−0.03%/year, −0.96%/year, −0.43%/year) and did not significantly differ from the normal physiological decline of −0.66%/year. The annual binding potential mean changes of the P group (−9.6%/year, −13%/year, −11%/year) significantly differed not only from the N group but also from the physiological decline. No significant difference was shown between P0 and P1 groups.ConclusionThe DaTsoft3D^® quantification software permits to split up two groups according to the evolution of the dopamine transporter density with a significant difference in the binding potential mean annual rate.