PET imaging of cardiomyocyte apoptosis in a rat myocardial infarction model

Cardiomyocyte apoptosis has been observed in several cardiovascular diseases and contributes to the subsequent cardiac remodeling processes and progression to heart failure. Consequently, apoptosis imaging is helpful for noninvasively detecting the disease progression and providing treatment guidance. Here, we tested ¹⁸F-labeled 2-(5-fluoropentyl)-2-methyl-malonic acid (¹⁸F-ML-10) and ¹⁸F-labeled 2-(3-fluoropropyl)-2-methyl-malonic acid (¹⁸F-ML-8) for apoptosis imaging in rat models of myocardial infarction (MI) and compared them with ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG). MI was induced in Sprague-Dawley rats by permanent left coronary artery ligation. Procedural success was confirmed by echocardiography and positron emission tomography (PET) imaging with ¹⁸F-FDG. In vivo PET imaging with ¹⁸F-ML-10 and ¹⁸F-ML-8 was performed in the MI models at different time points after operation. Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assays and immunohistochemical analyses were used to evaluate myocardial apoptosis. In vitro cell binding assays were performed to validate ¹⁸F-ML-8 binding to apoptotic cardiomyocytes. PET imaging demonstrated high ¹⁸F-ML-10 and ¹⁸F-ML-8 uptake where ¹⁸F-FDG uptake was absent. The focal accumulation of the two tracers was high on days 1 and 3 but was not notable on days 5 and 7 after surgery. The infarct-to-lung uptake ratio was 4.29?±?0.30 for ¹⁸F-ML-10 and 3.51?±?0.18 for ¹⁸F-ML-8 (n?=?6, analyzed by averaging the uptake ratios on postoperative days 1 and 3, P?<?0.05). The TUNEL results showed that myocardial cell apoptosis was closely related to the focal uptake of the apoptotic tracers in the infarct area. In addition, the apoptosis rates calculated from the TUNEL results were better correlated with ¹⁸F-ML-8 uptake than with ¹⁸F-ML-10 uptake. Ex vivo cell binding assays demonstrated that ¹⁸F-ML-8 accumulated in apoptotic cells but not in necrotic or normal cells. PET imaging using ¹⁸F-ML-10 or ¹⁸F-ML-8 allows the noninvasive detection of myocardial apoptosis in the early phase. In addition, ¹⁸F-ML-8 may be better than ¹⁸F-ML-10 for apoptosis imaging. We propose that PET imaging with ¹⁸F-ML-10 or ¹⁸F-ML-8 combined with ¹⁸F-FDG is an alternative for detecting and assessing MI.     

Cost-effective PET investigations in oncology

The authors have reviewed the financial considerations of oncological FDG PET examinations by the guidelines of the Health Care Financing Administration (USA). By critical assessment of large number of clinical investigations,the cost-effectiveness of FDG PET scans has been confirmed in the following cases: differential diagnosis of solitary pulmonary nodule, diagnosis,staging and restaging of non-small cell lung cancer, colorectal cancer, malignant lymphomas, melanoma malignum, esophageal neoplasms and cancers of the head and neck. The role of this method in breast cancer is currently under intensive investigation. Due to the correct staging, PET examinations in these indications enable the clinicians to choose the optimal treatment ensuring the maximum probability of recovery and being cost-effective as unnecessary medical interventions become avoidable.     

Targeted molecular imaging of angiogenesis in PET and SPECT: a review

Over the past few decades, there have been significant advancements in the imaging techniques of positron emission tomography (PET) and single photon emission tomography (SPECT). These changes have allowed for the targeted imaging of cellular processes and the development of hybrid imaging systems (e.g., SPECT/CT and PET/CT), which provide both functional and structural images of biological systems. One area that has garnered particular attention is angiogenesis as it relates to ischemic heart disease and limb ischemia. Though the aforementioned techniques have benefits and consequences, they enable scientists and clinicians to identify regions that are vulnerable to or have been exposed to ischemic injury via non-invasive means. This literature review highlights the advancements in molecular imaging techniques and specific probes as they pertain to the process of angiogenesis in cardiovascular disease.     

Advanced adenoma diagnosis with FDG PET in a visibly normal mucosa: a case report

A 56 year old aromatherapist presented with advanced renal failure following chronic coal tar creosote vapour inhalation, and a chronic tubulo-interstitial nephritis was identified on renal biopsy. Following dialysis dependence occult inhalation continued, resulting in seizures, ataxia, cognitive impairment and marked generalised cerebral atrophy. We describe for the first time a case of creosote abuse by chronic vapour inhalation, resulting in significant morbidity. Use of the polycyclic aromatic hydrocarbon-containing wood preservative coal tar creosote is restricted by many countries due to concerns over environmental contamination and carcinogenicity. This case demonstrates additional toxicities not previously reported with coal tar creosote, and emphasizes the health risks of polycyclic aromatic hydrocarbon exposure.     

The temporal dynamics of reading: a PET study.

The temporal dynamics of evoked brain responses are normally characterized using electrophysiological techniques but the positron emission tomography study presented here revealed a temporal aspect of reading by correlating the duration a word remained in the visual field with evoked haemodynamic response. Three distinct types of effects were observed: in visual processing areas, there were linear increases in activity with duration suggesting that visual processing endures throughout the time the stimulus remains in the visual field. In right hemisphere areas, there were monotonic decreases in activity with increased duration which we relate to decreased attention for longer stimulus durations. In left hemisphere word processing areas there were inverted U-shaped dependencies between activity and word duration indicating that, after 400-600 ms, activity in word processing areas is progressively reduced if the word remains in the visual field. We conclude that these inverted U effects in left hemisphere language areas reflect the temporal dynamics of visual word processing and we highlight the implication of these effects for the design of activation studies involving reading.     

Synthesis and in vivo evaluation of a novel peripheral benzodiazepine receptor PET radioligand

The novel pyrazolopyrimidine ligand, N,N-diethyl-2-[2-(4-methoxyphenyl)-5,7-dimethyl-pyrazolo[1,5-a]pyrimidin-3-yl]-acetamide 1 (DPA-713), has been reported as a potent ligand for the peripheral benzodiazepine receptor (PBR) displaying an affinity of K(i)=4.7 nM. In this study, 1 was successfully synthesised and demethylated to form the phenolic derivative 6 as precursor for labelling with carbon-11 (t(1/2) = 20.4 min). [11C]1 was prepared by O-alkylation of 6 with [11C]methyl iodide. The radiochemical yield of [(11)C]1 was 9% (non-decay corrected) with a specific activity of 36 GBq/micromol at the end of synthesis. The average time of synthesis including formulation was 13.2 min with a radiochemical purity >98%. In vivo assessment of [11C]1 was performed in a healthy Papio hamadryas baboon using positron emission tomography (PET). Following iv administration of [11C]1, significant accumulation was observed in the baboon brain and peripheral organs. In the brain, the radioactivity peaked at 20 min and remained constant for the duration of the imaging experiment. Pre-treatment with the PBR-specific ligand, PK 11195 (5 mg/kg), effectively reduced the binding of [11C]1 at 60 min by 70% in the whole brain, whereas pre-treatment with the central benzodiazepine receptor ligand, flumazenil (1mg/kg), had no inhibitory effect on [11C]1 uptake. These results indicate that accumulation of [11C]1 in the baboon represents selective binding to the PBR. These exceptional in vivo binding properties suggest that [11C]1 may be useful for imaging the PBR in disease states. Furthermore, [11C]1 represents the first ligand of its pharmacological class to be labelled for PET studies and therefore has the potential to generate new information on the pathological role of the PBR in vivo.     

PET evaluation of pulmonary vascular permeability: a structure-function correlation

We compared regional measurements of the pulmonary transcapillary escape rate (rPTCER) for 68Ga-transferrin, obtained by positron emission tomography (PET), with morphometric data obtained from corresponding tissue samples in six anesthetized mechanically ventilated dogs, 1 h after oleic acid administration to either the left caudal lobe (0.015 ml/kg; Lobar group, n = 3) or the right atrium (0.08 ml/kg; Diffuse group, n = 3). Data were obtained from 48 regions in both injured and control lobes (right caudal lobes from the Lobar group). The volume density of edematous or hemorrhagic alveoli at the light-microscopic level was directly related to rPTCER (r = 0.82 for regions with rPTCER values less than 700 x 10(-4) min-1). Likewise, the relative surface of abnormal capillary endothelium and alveolar epithelium at the electron-microscopic level correlated well with rPTCER (r = 0.87 for regions with rPTCER less than 1,200 X 10(-4) min-1). We conclude that the rPTCER measurements obtained with PET reflect the morphological heterogeneity present in oleic acid-damaged lung tissue. Thus rPTCER measurements should be useful as a noninvasive quantitative index of lung injury. Furthermore, the tomographic image display of rPTCER may allow PET to be used as a "physiological probe" to guide tissue excision for later histological evaluation when lung injury is heterogeneous.     

PET as a potential tool for imaging molecular mechanisms of oncology in man

During the past ten years, positron emission tomography (PET) has been increasingly developed for imaging and quantifying molecular mechanisms in oncology. The technique uses radionuclides to label molecules, which can then be imaged in man. The inherent sensitivity and specificity of PET is unrivalled because it can image molecular interactions and pathways, providing quantitative kinetic information down to the subpicomolar level. This technology has the potential to answer a large number of important clinical questions in translational research in oncology. However, the challenges in the methodology are substantial. Molecular imaging has the potential to assist in the optimization of molecular-based targeted therapies in cancer and to investigate the function of the genome.     

Development of a safe and scalable route towards a tau PET tracer precursor

A scalable 5-step synthesis of the diazacarbazole derivative 1 used as tau PET tracer precursor is reported. Key features of this synthesis include a Buchwald-Hartwig amination, a Pd catalyzed CH activation and a Suzuki-Miyaura cross-coupling.     

A benzenesulfonamide derivative as a novel PET radioligand for CXCR4

CXCR4 is involved in various diseases such as inflammation, tumor growth, and cancer metastasis through the interaction with its natural endogenous ligand, chemokine CXCL12. In an effort to develop imaging probes for CXCR4, we developed a novel small molecule CXCR4-targeted PET agent (compound 5) by combining our established benzenesulfonamide scaffold with a labeling component by virtue of click chemistry. 5 shows nanomolar affinity (IC₅₀ = 6.9 nM) against a known CXCR4 antagonist (TN14003) and inhibits more than 65% chemotaxis at 10 nM in vitro assays. Radiofluorinated compound 5 ([¹⁸F]5) demonstrates a competitive cellular uptake against CXCL12 in a dose-dependent manner. Further, microPET images of [¹⁸F]5 exhibits preferential accumulation of radioactivity in the lesions of λ-carrageenan-induced paw edema, human head and neck cancer orthotopic xenograft, and metastatic lung cancer of each mouse model.     

Evaluation of a dual-panel PET camera design to breast cancer imaging

We are developing a novel, portable dual-panel positron emission tomography (PET) camera dedicated to breast cancer imaging. With a sensitive area of ∼ 150 cm², this camera is based on arrays of lutetium oxyorthosilicate (LSO) crystals (1×1×3 mm³) coupled to 11×11-mm² position-sensitive avalanche photodiodes (PSAPD). GATE open source software was used to perform Monte Carlo simulations to optimize the parameters for the camera design. The noise equivalent counting (NEC) rate, together with the true, scatter, and random counting rates were simulated at different time and energy windows. Focal plane tomography (FPT) was used for visualizing the tumors at different depths between the two detector panels. Attenuation and uniformity corrections were applied to images.     

11C-labeling and preliminary evaluation of vortioxetine as a PET radioligand

Vortioxetine is a new multi-modal drug against major depressive disorder with high affinity for a range of different serotonergic targets in the CNS. We report the ¹¹C-labeling of vortioxetine with [¹¹C]MeI using a Suzuki-protocol that allows for the presence of an unprotected amine. Preliminary evaluation of [¹¹C]vortioxetine in a Danish Landrace pig showed rapid brain uptake and brain distribution in accordance with the pharmacological profile, all though an unexpected high binding in cerebellum was also observed. [¹¹C]vortioxetine displayed slow tracer kinetics with peak uptake after 60 min and with limited wash-out from the brain. Further studies are needed but this radioligand may prove to be a valuable tool in unraveling the clinical effects of vortioxetine.     

Update on latest advances in time-of-flight PET

This paper provides an update on time-of-flight (TOF) PET with a focus on latest hardware developments leading to current commercial PET/CT instruments. We describe advances in scintillator development, new photosensors and associated electronics readout, and detector designs for utilization in complete systems. Next, we introduce the latest commercial PET/CT scanners based on the aforementioned technologies, and discuss the detector design choices made that are relevant to differences in the system performance. Finally, we end with a discussion of the latest performance benchmarks for improved timing in PET detectors, challenges in scaling this performance to a complete system, and the outlook towards achieving a sub-50 ps coincidence timing resolution (CTR) in a PET detector.     

Poisson Noise Obscures Hypometabolic Lesions in PET

The technology of fluoro-deoxyglucose positron emission tomography (PET) has drastically increased our ability to visualize the metabolic process of numerous neurological diseases. The relationship between the methodological noise sources inherent to PET technology and the resulting noise in the reconstructed image is complex. In this study, we use Monte Carlo simulations to examine the effect of Poisson noise in the PET signal on the noise in reconstructed space for two pervasive reconstruction algorithms: the historical filtered back-projection (FBP) and the more modern expectation maximization (EM). We confirm previous observations that the image reconstructed with the FBP biases all intensity values toward the mean, likely due to spatial spreading of high intensity voxels. However, we demonstrate that in both algorithms the variance from high intensity voxels spreads to low intensity voxels and obliterates their signal to noise ratio. This finding has profound impacts on the clinical interpretation of hypometabolic lesions. Our results suggest that PET is relatively insensitive when it comes to detecting and quantifying changes in hypometabolic tissue. Further, the images reconstructed with EM visually match the original images more closely, but more detailed analysis reveals as much as a 40 percent decrease in the signal to noise ratio for high intensity voxels relative to the FBP. This suggests that even though the apparent spatial resolution of EM outperforms FBP, the signal to noise ratio of the intensity of each voxel may be higher in the FBP. Therefore, EM may be most appropriate for manual visualization of pathology, but FBP should be used when analyzing quantitative markers of the PET signal. This suggestion that different reconstruction algorithms should be used for quantification versus visualization represents a major paradigm shift in the analysis and interpretation of PET images.