Molecular imaging: The latest generation of contrast agents and tissue characterization techniques

Molecular Imaging technologies will have a profound impact on both basic research and clinical imaging in the near future. As the field covers many different specialties and scientific disciplines it is not possible to review all in a single article. In the current article we will turn our attention to those modalities that are either currently in use or in development for the medical imaging clinic.     

An Adipose Tissue Atlas: An Image-Guided Identification of Human-like BAT and Beige Depots in Rodents

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Plasmodium berghei: plasmodium perforin-like protein 5 is required for mosquito midgut invasion in Anopheles stephensi

During its life cycle the malarial parasite Plasmodium forms three invasive stages which have to invade different and specific cells for replication to ensue. Invasion is vital to parasite survival and consequently proteins responsible for invasion are considered to be candidate vaccine/drug targets. Plasmodium perforin-like proteins (PPLPs) have been implicated in invasion because they contain a predicted pore-forming domain. Ookinetes express three PPLPs, and one of them (PPLP3) has previously been shown to be essential for mosquito midgut invasion. In this study we show through phenotypic analysis of loss-of-function mutants that PPLP5 is equally essential for mosquito infection. Deltapplp5 ookinetes cannot invade midgut epithelial cells, but subsequent parasite development is rescued if the midgut is bypassed by injection of ookinetes into the hemocoel. The indistinguishable phenotypes of Deltapplp5 and Deltapplp3 ookinetes strongly suggest that these two proteins contribute to a common process.     

Characterization of the four isomers of 123I-CMICE-013: A potential SPECT myocardial perfusion imaging agent

Myocardial perfusion imaging (MPI) with single photon emission computed tomography (SPECT) is widely used in the assessment of coronary artery disease (CAD). We have developed ¹²³I-CMICE-013 based on rotenone, a mitochondrial complex I (MC-1) inhibitor, as a promising new MPI agent. Our synthesis results in a mixture of four species of ¹²³I-CMICE-013 A, B, C, D. In this study, we separated the four species and evaluated their biodistribution and imaging properties. The cold analogs ¹²⁷I-CMICE-013 A, B, C, D were isolated and characterized and their chemical structures proposed. Methods: ¹²³I-CMICE-013 was synthesized by radiolabeling rotenone with Na¹²³I in trifluoroacetic acid (TFA) with iodogen as the oxidizing agent at 60 °C for 45 min, and the four species were separated by RP-HPLC. The cold analogs ¹²⁷I-CMICE-013 A, B, C and D were isolated with a similar procedure and characterized by NMR and mass spectrometry. Biodistribution and microSPECT imaging studies were carried out on normal rats. Results: We propose the mechanism of the rotenone iodination and the structures of the four species. First, I⁺ forms an intermediate three-membered ring with 6′ and 7′ carbons. Second, the lone electron pair of the water molecule attacks the 6′ or 7′-carbon, following by the formation of 6′-OH, and 7′-I bonds as in major products C and D, or 6′-I and 7′-OH bonds as in minor products A and B. The weaker 6′-I bond in the intermediate prompts the nucleophilic attachment of water at the favorable 6′-carbon to generate C and D. MicroSPECT images of ¹²³I-CMICE-013 A, B, C, D in rats showed clear visualization of myocardium and little interference from lung and liver. The imaging time activity curves and biodistribution data showed complex profiles for the four isomers, which is not expected from the structure activity relationship theory. Conclusion: ^123/127I-CMICE-013 A and B are constitutional isomers with C and D, while A and C are diastereomers of B and D, respectively. Overall, the biological characteristics of the four species are not correlated perfectly with their molecular structures.     

Design and synthesis of tumor-targeting theranostic drug conjugates for SPECT and PET imaging studies

Theranostics will play a significant role in the next-generation chemotherapy. Two novel tumor-targeting theranostic drug conjugates, bearing imaging arms, were designed and synthesized. These theranostic conjugates consist of biotin as the tumor-targeting moiety, a second generation taxoid, SB-T-1214, as a potent anticancer drug, and two different imaging arms for capturing ^99mTc for SPECT (single photon emission computed tomography) and ⁶⁴Cu for PET (positron emission tomography). To explore the best reaction conditions for capturing radionuclides and work out the chemistry directly applicable to “hot” nuclides, cold chemistry was investigated to capture ¹⁸⁵Re(I) and ⁶³Cu(II) species as surrogates for ^99mTc and ⁶⁴Cu, respectively.     

Cardiac contraction motion compensation in gated myocardial perfusion SPECT: A comparative study

IntroductionCardiac contraction significantly degrades quality and quantitative accuracy of gated myocardial perfusion SPECT (MPS) images. In this study, we aimed to explore different techniques in motion-compensated temporal processing of MPS images and their impact on image quality and quantitative accuracy.Material and method50 patients without known heart condition underwent gated MPS. 3D motion compensation methods using Motion Freezing by Cedars Sinai (MF), Log-domain Diffeomorphic Demons (LDD) and Free-Form Deformation (FFD) were applied to warp all image phases to fit the end-diastolic (ED) phase. Afterwards, myocardial wall thickness, myocardial to blood pool contrast, and image contrast-to noise ratio (CNR) were measured in summed images with no motion compensation (NoMC) and compensated images (MF, LDD and FFD). Total Perfusion Defect (TPD) was derived from Cedars-Sinai software, on the basis of sex-specific normal limits.ResultLeft ventricle (LV) lateral wall thickness was reduced after applying motion compensation (p < 0.05). Myocardial to blood pool contrast and CNR in compensated images were greater than NoMC (p < 0.05). TPD_LDD was in good agreement with the corresponding TPD_MF (p = 0.13).ConclusionAll methods have improved image quality and quantitative performance relative to NoMC. LDD and FFD are fully automatic and do not require any manual intervention, while MF is dependent on contour definition. In terms of diagnostic parameters LDD is in good agreement with MF which is a clinically accepted method. Further investigation along with diagnostic reference standards, in order to specify diagnostic value of each technique is recommended.     

Dysplasie fibreuse des os en imagerie hybride TEMP/TDM

Fibrous dysplasia of the bone (FDB) is a benign congenital but non-hereditary bone disorder in which normal bone is replaced by pseudofibrous tissue containing an immature osteogenesis. It is frequently fortuitously discovered during a radiological or nuclear medicine scan. The main goal of this article is to give useful clinical and imaging information for the diagnosis of FDB in the daily practice of Nuclear Medicine.     

Ligand engineering for theranostic applications

Targeted therapy of cancer is considered as promising alternative approach to conventional chemotherapy and radiotherapy. Recent advancements in biotechnology have significantly improved the identification of novel radiopharmaceuticals allowing for more accurate imaging and therapeutic targeting of epithelial tumors. The successful development of radiotracers critically depends on the selection and validation of the tumor-specific target structure, the technical approach employed for the identification of a target-specific ligand, and the evaluation and improvement of the binding properties and the pharmacokinetic profile of the ligand by biotechnological procedures or chemical modification, respectively. Employing rational design of a quinoline-based fibroblast activation protein inhibitor (FAPI) and ‘high-through put’ display technology using a sunflower trypsin inhibitor1-based peptide library, several FAPI derivatives and a novel αvβ6 integrin-binding peptide (SFITGv6) were identified. FAPI and SFITGv6 represent powerful radiopharmaceuticals for diagnostic imaging and/or endoradiotherapy of FAP- and αvβ6 integrin-expressing epithelial tumors, respectively.     

Diphenylpropynone derivatives as probes for imaging β-amyloid plaques in Alzheimer's brains

A new series of diphenylpropynone (DPP) derivatives for use in vivo to image β-amyloid (Aβ) plaques in the brain of patients with Alzheimer’s disease (AD) were synthesized and characterized. Binding experiments in vitro revealed high affinity for Aβ (1-42) aggregates at a K_i value ranging from 6 to 326 nM. Furthermore, specific labeling of plaques was observed in sections of brain tissue from Tg2576 transgenic mice stained using one of the compounds, 1. In biodistribution experiments with normal mice, [¹²⁵I]1 displayed moderate uptake (1.55% ID/g at 2 min) and clearance from the brain with time (0.76 ID/g at 60 min). Taken together, DPP can serve as a new molecular scaffold for developing novel Aβ imaging agents by introducing appropriate substituted groups.