Project description:ObjectiveRecent advances in the fundamental understanding of the complex biology of prostate cancer have provided an increasing number of potential targets for imaging and treatment. The imaging evaluation of prostate cancer needs to be tailored to the various phases of this remarkably heterogeneous disease.ConclusionIn this article, I review the current state of affairs on a range of PET radiotracers for potential use in the imaging evaluation of men with prostate cancer.
Project description:Colorectal cancer is one of the top causes of cancer and cancer-related deaths worldwide. The prognosis of metastatic colorectal cancer is poor and treatment options are limited. Many patients will run out of treatment options before they become medically unfit for therapy. As such, there is a need to expand upon the current understanding of disease biology as well as drug resistance mechanisms in order to create new approaches for therapy. In this review article, we will discuss the mechanistic rationale and clinical data for new drugs and therapeutic combinations under development for metastatic colorectal cancer.
Project description:Purpose of reviewThe purpose of this paper is to provide a focused update on recent advances in non-18F-FDG radiotracers for myocardial inflammatory diseases, with a focus on cardiac sarcoidosis and myocarditis.Recent findingsNovel radiotracers targeting molecular features of inflammation have the potential to visualize underlying molecular mechanisms key to the pathogenesis of inflammatory cardiomyopathies such as sarcoidosis and myocarditis. These radiotracers may provide unique opportunities for improved mechanistic insight, higher specificity, and better quantification of disease activity, as well as potential for guidance and monitoring of immunomodulatory therapies.SummaryNovel radiotracers provide unique possibilities in diagnosis, prognostic performance, and therapy guidance for cardiac sarcoidosis and myocarditis.
Project description:ObjectiveThe aim of the present study was to characterize the cortical source generators evoked by experimental tonic pain.MethodsElectroencephalography (EEG) was recorded on two separate days during rest and with immersion of the hand in ice water for 2 minutes (cold pressor test). Exact low-resolution brain electromagnetic tomography source localization was performed in 31 healthy volunteers to characterize the cortical source generators.ResultsReliability was high in all eight frequency bands during rest and cold pressor conditions (intraclass coefficients =0.47-0.83 in the cingulate and insula). Tonic pain increased cortical activities in the delta (1-4 Hz), theta (4-8 Hz), beta1 (12-18 Hz), beta2 (18-24 Hz), beta3 (24-32 Hz), and gamma (32-60 Hz) bands (all P<0.011) in widespread areas mainly in the limbic system, whereas decreased cortical activities were found in cingulate and pre- and postcentral gyri in the alpha2 (10-12 Hz) band (P=0.007). The pain intensity was correlated with cingulate activity in the beta2, beta3, and gamma bands (all P<0.04).ConclusionSource localization of EEG is a reliable method to estimate cortical source generators. Activities in different brain regions, mainly in the limbic system, showed fluctuations in various frequency bands. Cingulate changes were correlated with pain intensity.SignificanceThis method might add information to the objective assessment of the cortical pain response in future experimental pain studies.
Project description:Mitochondrial dysfunction has been indicated in neurodegenerative and other disorders. The mitochondrial complex I (MC-I) of the electron transport chain (ETC) on the inner membrane is the electron entry point of the ETC and is essential for the production of reactive oxygen species. Based on a recently identified β-keto-amide type MC-I modulator from our laboratory, an 18F-labeled positron emission tomography (PET) tracer, 18F-2, was prepared. PET/CT imaging studies demonstrated that 18F-2 exhibited rapid brain uptake without significant wash out during the 60 min scanning time. In addition, the binding of 18F-2 was higher in the regions of the brain stem, cerebellum, and midbrain. The uptake of 18F-2 can be significantly blocked by its parent compound. Collectively, the results strongly suggest successful development of MC-I PET tracers from this chemical scaffold that can be used in future mitochondrial dysfunction studies of the central nervous system.
Project description:The molecular imaging of apoptosis remains an important method for the diagnosis and monitoring of the progression of certain diseases and the evaluation of the efficacy of anticancer apoptosis-inducing therapies. Among the multiple biomarkers involved in apoptosis, activated caspase-3 is an attractive target, as it is the most abundant of the executioner caspases. Nuclear imaging is a good candidate, as it combines a high depth of tissue penetration and high sensitivity, features necessary to detect small changes in levels of apoptosis. However, designing a caspase-3 radiotracer comes with challenges, such as selectivity, cell permeability and transient caspase-3 activation. In this review, we discuss the different caspase-3 radiotracers for the imaging of apoptosis together with the challenges of the translation of various apoptosis-imaging strategies in clinical trials.
Project description:Matrix metalloproteinase-12 (MMP-12) is highly upregulated in several inflammatory diseases, including abdominal aortic aneurysm (AAA). Here we report four novel 99mTc-labeled radiotracers derived from a highly selective competitive MMP-12 inhibitor. These tracers in their 99gTc version were assessed in vitro on a set of human metalloproteases and displayed high affinity and selectivity toward MMP-12. Their radiolabeling with 99mTc was shown to be efficient and stable in both buffer and mouse blood. The tracers showed major differences in their biodistribution and blood clearance. On the basis of its in vivo performance, [99mTc]-1 was selected for evaluation in murine AAA, where MMP-12 gene expression is upregulated. Autoradiography of aortae at 2 h postinjection revealed high uptake of [99mTc]-1 in AAA relative to adjacent aorta. Tracer uptake specificity was demonstrated through in vivo competition. This study paves the way for further evaluation of [99mTc]-1 for imaging AAA and other MMP-12-associated diseases.
Project description:Physical frailty and sarcopenia (PF&S) recapitulates all the hallmarks of aging and has become a focus in geroscience. Factors spanning muscle-specific processes (e.g., mitochondrial dysfunction in skeletal myocytes) to systemic changes (e.g., inflammation and amino acid dysmetabolism) have been pinpointed as possible contributors to PF&S pathophysiology. However, the search for PF&S biomarkers allowing the early identification and tracking of the condition over time is ongoing. This is mainly due to the phenotypic heterogeneity of PF&S, its unclear pathophysiology, and the frequent superimposition of other age-related conditions. Hence, presently, the identification of PF&S relies upon clinical, functional, and imaging parameters. The adoption of multi-marker approaches (combined with multivariate modeling) has shown great potential for addressing the complexity of PF&S pathophysiology and identifying candidate biological markers. Well-designed longitudinal studies are necessary for the incorporation of reliable biomarkers into clinical practice and for unveiling novel targets that are amenable to interventions.
Project description:The increasing use of amyloid PET in Alzheimer's disease research and clinical trials has motivated efforts to standardize methodology. We compared retention of the (11)C radiotracer Pittsburgh Compound B (PiB) and that of two (18)F amyloid radiotracers (florbetapir and flutemetamol) using two study populations. We also examined the feasibility of converting between tracer-specific measures, using PiB as the common link between the two (18)F tracers.One group of 40 subjects underwent PiB and flutemetamol imaging sessions and a separate group of 32 subjects underwent PiB and florbetapir imaging sessions. We compared cortical and white matter retention for each (18)F tracer relative to that of PiB, as well as retention in several reference regions and image analysis methods. Correlations between tracer pairs were used to convert tracer-specific threshold values for amyloid positivity between tracers.Cortical retention for each pair of tracers was strongly correlated regardless of reference region (PiB-flutemetamol, ??=?0.84-0.99; PiB-florbetapir, ??=?0.83-0.97) and analysis method (??=?0.90-0.99). Compared to PiB, flutemetamol had higher white matter retention, while florbetapir had lower cortical retention. Two previously established independent thresholds for amyloid positivity were highly consistent when values were converted between tracer pairs.Despite differing white and grey matter retention characteristics, cortical retention for each (18)F tracer was highly correlated with that of PiB, enabling conversion of thresholds across tracer measurement scales with a high level of internal consistency. Standardization of analysis methods and measurement scales may facilitate the comparison of amyloid PET data obtained using different tracers.
Project description:The development of a positron emission tomography (PET)/magnetic resonance spectroscopy (MRS) hybrid imaging agent allows for functional imaging by both methods with a single imaging agent. Enzyme substrates that are cleaved to form two metabolites present an interesting opportunity, as the unique metabolites generated might each be detected by a different modality. To be successful, such enzyme substrates would require administration of doses that (a) reach the in vivo target tissue at concentrations necessary for MRS imaging, (b) do not show substrate inhibition of tissue uptake or enzymatic activity, and (c) provide PET images that still reflect the action of the enzyme. We report in vitro and in vivo proof-of-concept studies of a carbon-11 small molecule substrate for brain monoamine oxidases that, upon enzyme-mediated cleavage, produces two metabolites, one detectable by PET and the other by MRS.