Small Animal PET Scanner Research Articles

Automatic labeling method for injectable 15O-oxygen using hemoglobin-containing liposome vesicles and its application for measurement of brain oxygen consumption by PET

The aim of this study was to develop an injectable (15)O-O(2) system using hemoglobin-containing vesicles (HbV), a type of artificial red blood cell, and to investigate the feasibility of (15)O(2)-labeled HbV ((15)O(2)-HbV) to measure cerebral metabolic rate of oxygen (CMRO(2)) in rats. The direct bubbling method was combined with vortexing to enhance labeling efficiency of HbV with (15)O-O(2) gas. L-Cysteine was added as a reductant to protect hemoglobin molecules in HbV from oxidation at different concentrations, and labeling efficiencies were also compared. Measurement of cerebral blood flow (CBF) and CMRO(2) in five normal rats was performed using a small animal PET scanner after the injection of H(2)(15)O and (15)O(2)-HbV to evaluate the precision of hemodynamic parameters quantitatively. The labeling efficiency of HbV was significantly increased when vortexing and bubbling were combined compared with the simple bubbling method (P<.05). The most efficient method for labeling was bubbling of (15)O-O(2) combined with vortexing and the addition of 2.8 mM L-cysteine in HbV solution. The mean radioactivity of 214.4+/-7.8 MBq/mL HbV was obtained using this method. PET scans using (15)O(2)-HbV and H(2)(15)O yielded a mean CMRO(2) value of 6.8+/-1.4 (mL/min per 100 g) in rats with normal CBF of 51.4+/-7.9 (mL/min per 100 g). Addition of l-cysteine to HbV and simple direct bubbling of (15)O-O(2) gas combined with vortexing was the most efficient method for preparation of (15)O(2)-HbV. The present injectable system using (15)O(2)-HbV was successfully utilized to measure CMRO(2) in rats, indicating that this new method could be useful for animal models to measure oxygen metabolism in the brain.

Design of silicon-based misonidazole analogues and 18F-radiolabelling

Development of new (18)F-labeled tracers for positron emission tomography (PET) imaging is increasingly important. Herein, we described the synthesis of silicon analogues of [(18)F]fluoromisonidazole in order to develop new radiolabelled compounds for the detection of tumour hypoxic domain. Their stabilities and their in vivo biodistribution were evaluated. (18)F-labeled silicon-based misonidazole analogues were synthesized by alkylating 2-nitroimidazole with alkyloxy-(3-chloropropyl)dialkyl or diarylsilane. These intermediates were labeled with [(18)F]F(-) with a mixture of K(18)F and Kryptofix (K222) in acetonitrile as standard condition. PET imaging was performed using a dedicated small animal PET scanner. (18)F-labeled silicon-based misonidazole analogues were easily synthesized in three steps. The hydrolytic and radiolytic stability of these new fluorosilanes depend on the steric hindrance at the silicon center. Indeed, partial uptake of dimethylfluorosilane [(18)F]2a(1-(3-(Fluorodimethylsilyl)propyl)-2-nitro-1H-imidazole) in tumor hypoxic area was observed but defluorination also appeared. Moreover, PET studies indicated that, owing to its high lipophilicity, the most stable dinaphtylfluorosilane [(18)F]2d is retained mainly by the lungs. We have described an efficient and versatile approach for the synthesis of (18)F-labeled, silicon-based misonidazole analogues. PET imaging of one of these compounds revealed that hypoxia could be detected. Controlling the biodistribution of (18)F-labeled silicon-based misonidazole analogues will require additional studies.

A High-Sensitivity Small-Animal PET Scanner: Development and Initial Performance Measurements

An important challenge in positron emission tomography (PET) is the development of dedicated small-animal PET (muPET) systems having high sensitivity. In this paper, we investigate the use of an opposing pair of large-area detectors having high detection efficiency and moderate depth-of-interaction resolution in a compact scanner geometry for achieving a high system sensitivity. Substantial resolution degradations created by this hardware configuration, on the other hand, are corrected for by applying model-based image reconstruction. We have developed a prototype scanner adopting this design and evaluated its performance properties. Our results show that the prototype can achieve a central sensitivity of ~28.2% when using an energy window (EW) of 250-750 keV and a coincidence time window (CW) of 10 ns. When decreasing the EW to 400-750 keV, the central sensitivity still remains high at ~14.4%. Over the typical ranges of radioactivity used in PET rodent imaging with [18F]fluorodeoxyglucose (FDG), the prototype provides noise-equivalent count rates (NECRs) that are considerably higher than other muPET systems. For a mouse/rat-sized cylinder, we obtain a peak NECR of ~ 1.86/1.2 Mcps at ~32/40 MBq when using a 250/350-750 keV EW and a 6 ns CW. Using a resolution phantom, we obtain an average FWHM (full width at the half-maximum) of 1.79 mm for 1.35 mm-diameter rod sources when the axis of the phantom is vertical to the detectors of the prototype. This is consistent with the 1.2 mm FWHM image resolution previously obtained by using simulation data. The prototype also generates FDG rat images having good visual quality.

Impact on Image Noise of Incorporating Detector Blurring into Image Reconstruction for a Small Animal PET Scanner.

We study the noise characteristics of an image reconstruction algorithm that incorporates a model of the non-stationary detector blurring (DB) for a mouse-imaging positron emission tomography (PET) scanner. The algorithm uses ordered subsets expectation maximization (OSEM) image reconstruction, which is used to suppress statistical noise. Including the non-stationary detector blurring in the reconstruction process (OSEM(DB)) has been shown to increase contrast in images reconstructed from measured data acquired on the fully-3D MiCES PET scanner developed at the University of Washington. As an extension, this study uses simulation studies with a fully-3D acquisition mode and our proposed FORE+OSEM(DB) reconstruction process to evaluate the volumetric contrast versus noise trade-offs of this approach. Multiple realizations were simulated to estimate the true noise properties of the algorithm. The results show that incorporation of detector blurring (FORE+OSEM(DB)) into the reconstruction process improves the contrast/noise trade-offs compared to FORE+OSEM in a radially dependent manner. Adding post reconstruction 3D Gaussian smoothing to FORE+OSEM and FORE+OSEM(DB) reduces the contrast versus noise advantages of FORE+OSEM(DB).

Energy, Timing and Position Resolution Studies With 16-Pixel Silicon Photomultiplier Matrices for Small Animal PET

A high resolution small animal PET scanner that employs Silicon Photomultiplier (SiPM) matrices as photodetectors is under development at the University of Pisa and INFN Pisa. The first SiPM matrices fabricated by the Center for Scientific and Technological Research, FBK-irst (Trento, Italy), are being evaluated for this purpose. The devices are composed of 16 (4 times4) pixel elements of 1 mmtimes1 mm in a common substrate. The first tests have been carried out employing the ASIC MAROC2 for the readout. Energy and timing resolution, and position determination tests have been performed coupling both pixellated and continuous LYSO scintillator crystals to the matrix, and the results have been compared with the ones obtained for single SiPMs. The first tests on position determination with continuous crystals and SiPM matrices have been performed. An intrinsic spatial resolution of 0.61 mm FWHM has been obtained.

Experimental characterization and system simulations of depth of interaction PET detectors using 0.5 mm and 0.7 mm LSO arrays

Small animal PET scanners may be improved by increasing the sensitivity, improving the spatial resolution and improving the uniformity of the spatial resolution across the field of view. This may be achieved by using PET detectors based on crystal elements that are thin in the axial and transaxial directions and long in the radial direction, and by employing depth of interaction (DOI) encoding to minimize the parallax error. With DOI detectors, the diameter of the ring of the PET scanner may also be decreased. This minimizes the number of detectors required to achieve the same solid angle coverage as a scanner with a larger ring diameter and minimizes errors due to non-collinearity of the annihilation photons. In this study, we characterize prototype PET detectors that are finely pixelated with individual LSO crystal element sizes of 0.5 mm × 0.5 mm × 20 mm and 0.7 mm × 0.7 mm × 20 mm, read out at both ends by position sensitive avalanche photodiodes (PSAPDs). Both a specular reflector and a diffuse reflector were evaluated. The detectors were characterized based on the ability to clearly resolve the individual crystal elements, the DOI resolution and the energy resolution. Our results indicate that a scanner based on any of the four detector designs would offer improved spatial resolution and more uniform spatial resolution compared to present day small animal PET scanners. The greatest improvements to spatial resolution will be achieved when the detectors employing the 0.5 mm × 0.5 mm × 20 mm crystals are used. Monte Carlo simulations were performed to demonstrate that 2 mm DOI resolution is adequate to ensure uniform spatial resolution for a small animal PET scanner geometry using these detectors. The sensitivity of such a scanner was also simulated using Monte Carlo simulations and was shown to be greater than 10% for a four ring scanner with an inner diameter of 6 cm, employing 20 detectors per scanner ring.

Registration Method for the Detection of Tumors in Lung and Liver Using Multimodal Small Animal Imaging

Small animal PET scanning with <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">18</sup> F-FDG has been increasingly used in the studies using murine tumor models. The aim of this study was to obtain multimodal tumor images with the use of small animal PET and clinical CT by using hardware guidance and a registration method. PET imaging studies were performed with a dedicated small animal PET scanner. Static PET images of mice with liver and lung tumors were scanned for 20 minute by the use of hardware guidance with 1% activity of the injected dose. The CT images obtained with the use of a clinical CT scanner can be used to improve the anatomical localization of uptake in PET images. <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">124</sup> I -FIAU-PET was obtained from mice containing an orthotopic hepatocellular carcinoma (HCC). Contrast enhanced CT images were obtained at three hours after injection of contrast agent. The PET and CT images were fused using hardware fiducial markers that were manually identified in both data sets. The PET and CT images were precisely registered by the use of a small animal contour point in both data sets to perform a point-based rigid registration. The registered images in the HCC model and a lung metastatic tumor model showed good agreement of tumor region on the both PET and CT images. The use of PET and contrast enhanced CT allowed a precise and improved detection of tumors in liver and lung models. Multimodal imaging with small animal PET and clinical CT images was useful in the detection of metastatic tumors and this multimodal imaging registration method can improve the quantitative accuracy and interpretation of tracer.

First results in the application of silicon photomultiplier matrices to small animal PET

A very high resolution small animal PET scanner that employs matrices of silicon photomultipliers as photodetectors is under development at the University of Pisa and INFN Pisa. The first SiPM matrices composed of 16 ( 4 × 4 ) 1 mm × 1 mm pixel elements on a common substrate have been produced at FBK-irst, and are being evaluated for this application. The MAROC2 ASIC developed at LAL-Orsay has been employed for the readout of the SiPM matrices. The devices have been tested with pixelated and continuous LYSO crystals. The results show the good performance of the matrices and lead to the fabrication of matrices with 64 SiPM elements.

Simultaneous attenuation and scatter corrections in small animal PET imaging

The aim of this work is to simultaneously correct for attenuation and scatter in PET by analytically assessing the distribution of the scattered photons using the emission and the transmission images, the probability of scatter interactions and the detection efficiency. Above the usual lower energy threshold of 350 keV, the attenuated photons are dominantly those which have undergone a Compton scattering. By considering that each pixel in the image is the measurement of the transmitted photons through the subject, added to the contribution from the other sources by means of their scatter at this position, a simple equation is established accounting for the primaries by simultaneously correcting the data for attenuation and scatter for all emitting sources. This new method was applied in Monte Carlo simulated and measured data with the Sherbrooke small animal PET scanner in line sources, hot spot phantoms, and in rat hearts and tumors, and was compared to the approach developed by Watson et al.

New MRI, 18F-DOPA and 11C-(+)-α-dihydrotetrabenazine templates for Macaca fascicularis neuroimaging: Advantages to improve PET quantification

Normalization of neuroimaging studies to a stereotaxic space allows the utilization of standard volumes of interest (VOIs) and voxel-based analysis (SPM). Such spatial normalization of PET and MRI studies requires a high quality template image. The aim of this study was to create new MRI and PET templates of 18F-DOPA and 11C-(+)-α-dihydrotetrabenazine (11C-DTBZ) of the Macaca fascicularis brain, an important animal model of Parkinson's disease. MRI template was constructed as a smoothed average of the scans of 15 healthy animals, previously transformed into the space of one representative MRI. In order to create the PET templates, 18F-DOPA and 11C-DTBZ PET of the same subjects were acquired in a dedicated small animal PET scanner and transformed to the created MRI template space. To validate these templates for PET quantification, parametric values obtained with a standard VOI-map applied after spatial normalization to each template were statistically compared to results computed using individual VOIs drawn for each animal. The high correlation between both procedures validated the utilization of all the templates, improving the reproducibility of PET analysis. To prove the utility of the templates for voxel-based quantification, dopamine striatal depletion in a representative monkey treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was assessed by SPM analysis of 11C-DTBZ PET. A symmetric reduction in striatal 11C-DTBZ uptake was detected in accordance with the induced lesion. In conclusion, templates of M. fascicularis brain have been constructed and validated for reproducible and automated PET quantification. All templates are electronically available via the internet.

Non-Invasive Imaging of Acute Renal Allograft Rejection in Rats Using Small Animal 18F-FDG-PET

BackgroundAt present, renal grafts are the most common solid organ transplants world-wide. Given the importance of renal transplantation and the limitation of available donor kidneys, detailed analysis of factors that affect transplant survival are important. Despite the introduction of new and effective immunosuppressive drugs, acute cellular graft rejection (AR) is still a major risk for graft survival. Nowadays, AR can only be definitively by renal biopsy. However, biopsies carry a risk of renal transplant injury and loss. Most important, they can not be performed in patients taking anticoagulant drugs.Methodology/Principal FindingsWe present a non-invasive, entirely image-based method to assess AR in an allogeneic rat renal transplantation model using small animal positron emission tomography (PET) and 18F-fluorodeoxyglucose (FDG). 3 h after i.v. injection of 30 MBq FDG into adult uni-nephrectomized, allogeneically transplanted rats, tissue radioactivity of renal parenchyma was assessed in vivo by a small animal PET-scanner (post operative day (POD) 1,2,4, and 7) and post mortem dissection. The mean radioactivity (cps/mm3 tissue) as well as the percent injected dose (%ID) was compared between graft and native reference kidney. Results were confirmed by histological and autoradiographic analysis. Healthy rats, rats with acute CSA nephrotoxicity, with acute tubular necrosis, and syngeneically transplanted rats served as controls. FDG-uptake was significantly elevated only in allogeneic grafts from POD 1 on when compared to the native kidney (%ID graft POD 1: 0.54±0.06; POD 2: 0.58±0.12; POD 4: 0.81±0.06; POD 7: 0.77±0.1; CTR: 0.22±0.01, n = 3–28). Renal FDG-uptake in vivo correlated with the results obtained by micro-autoradiography and the degree of inflammatory infiltrates observed in histology.Conclusions/SignificanceWe propose that graft FDG-PET imaging is a new option to non-invasively, specifically, early detect, and follow-up acute renal rejection. This method is potentially useful to improve post-transplant rejection monitoring.

Contribution of normalization to image noise for the Siemens Inveon small-animal PET scanner

Due to the large number of detector elements (25,600 crystals) and lines of response (LOR) (88,453,120), normalization of the Siemens Inveon small-animal PET scanner can introduce additional image noise when using the standard, individual LOR-based normalization (ILORNORM) of 10 h scan duration. Recently, component-based normalization (CNORM) has been made available for this scanner. The aim of this study was to compare the performance of both normalization algorithms and to determine the minimum time needed for a normalization scan. Normalization scans of 1 min up to 115 h were performed. Reconstructed image noise was determined using the FDG-filled NEMA NU-4 small-animal PET image quality phantom. CNORM significantly reduced image noise as compared to ILORNORM. For CNORM, the scan duration could even be reduced to 10 min without deterioration of reconstructed image quality. Such a short scan duration implies that scanner normalization can easily be incorporated in daily or weekly quality control procedures.

Assessment of Airway Distribution of Transnasal Solutions in Mice by PET/CT Imaging

Transnasal administration is one of the most common routes for allergen challenge in mouse models of airway diseases. Although this technique is widely used, neither the amount of allergen that reaches the lung nor its airway distribution has been well established. We used positron emission tomography (PET) and computed tomography (CT) to examine the anatomical distribution of a solution containing a tracer immediately after transnasal delivery and to determine the possible influence of age and administered volume. Forty-six female BALB/c mice were divided into three groups according to instillation volume and age: (A) 15 microl, 8-10 weeks old (N = 10), (B) 30 microl, 8-10 weeks old (N = 20), and (C) 30 microl, 32 weeks old (N = 16). Anesthetized animals underwent a dynamic scan in a dedicated small-animal PET scanner immediately after transnasal administration of a solution containing (18)FDG. Regions of interest were used to obtain quantitative data. Animals were also imaged with a small-animal CT scanner to obtain complementary anatomical information. Mean +/- SD (5.69 +/- 4.51%) of the solution administered reached the lungs in group A, 41.84 +/- 8.03% in group B, and 36.65 +/- 16.15% in group C. A comparable percentage was delivered to the left and right lungs in all the groups. Analysis of variance revealed a significant difference between the groups in the proportion of the solution that reached the lungs depending on the injection volume (P < 0.001), but not depending on animal age. In this first report on quantitative imaging by PET and CT in small animals, we confirmed the suitability of the transnasal route with an instilled volume of 30 microl delivering fluids into the lower airways, although only about 40% of the dose reaches the lungs.

Small Animal PET in Oncology: The Road from Bench to Bedside

Positron emission tomography (PET) is routinely performed in patients with cancer for disease staging, assessment of relapse, and evaluation of therapy response. In addition to its well-established value in human malignant diseases, the use of special small animal PET (SA-PET) scanners have allowed for accurate assessment of small animals bearing human tumors. This application of PET provides whole-body, noninvasive, functional data of tumor lesions and can be used to assess abnormalities in the metabolic pathways of cancer, such as uncontrolled proliferation, increased apoptosis, and angiogenesis. Several positron-emitting tracers labeled with 18-fluorine and 11-carbon are currently available for PET studies to image abnormal biologic pathways of tumors. Moreover, SA-PET can be used to evaluate tumor-cell-receptor expression, a sign of tumor cells differentiation that is relevant for planning targeted therapies. Another advantage of SA-PET is the quantitation capability: Semiquantitation of the tumor activity can be performed at each scan and compared in the same animal over time to monitor tumor growth or to assess the response to new therapies. This review focuses on the applications of SA-PET for the visualization of the pathophysiologic pathways of tumor cells.

111In-LLP2A-DOTA Polyethylene Glycol–Targeting α4β1 Integrin: Comparative Pharmacokinetics for Imaging and Therapy of Lymphoid Malignancies

N-[[4-[[[(2-ethylphenyl)amino]carbonyl]amino]phenyl]acetyl]-N(epsilon)-6-[(2E)-1-oxo-3-(3-pyridinyl-2-propenyl)]-l-lysyl-l-2-aminohexanedioyl-(1-amino-1-cyclohexane)carboxamide (LLP2A) is a high-affinity, high-specificity peptidomimetic ligand (inhibitory concentration of 50% = 2 pM) that binds the activated alpha4beta1 integrin found on a variety of malignant lymphoid cell lines. To better determine whether this ligand holds promise for imaging and therapy in lymphoid malignancies, 6 LLP2A derivatives, as LLP2A-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (LLP2A-DOTA) and LLP2A-DOTA-polyethylene glycol (LLP2A-DOTA-PEG), were designed, synthesized, and radiolabeled with (111)In. Comparative pharmacokinetic studies in mice with Raji B-cell lymphoma xenografts were then complemented by small-animal PET of the lead molecular LLP2A format using (64)Cu-LLP2A-11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane ((64)Cu-LLP2A-CB-TE2A). LLP2A-DOTA and LLP2A-CB-TE2A were prepared using solid-phase synthesis; LLP2A-DOTA-PEG(2,000), LLP2A-DOTA-PEG(5,000), LLP2A-DOTA-PEG(10,000), (LLP2A-DOTA)(2)PEG(10,000), and (LLP2A-DOTA)(4)PEG(10,000) were prepared by PEGylation. (111)In radiolabeling of DOTA and (64)Cu radiolabeling of CB-TE2A conjugates yielded 370-1,850 and 3,700-7,400 kBq/microg (10-50 and 100-200 microCi/microg), respectively. The pharmacokinetics of the six (111)In radioconjugates were studied in vivo using biodistribution data (4 and 24 h) and whole-body autoradiography (24 h) in mice with Raji tumor xenografts. (64)Cu-LLP2A-CB-TE2A was imaged (4 and 24 h) on a small-animal PET scanner in the same mouse model. The highest tumor uptake in pharmacokinetic studies was obtained with LLP2A-DOTA and (LLP2A-DOTA)(4)-PEG(10,000). For (111)In-LLP2A-DOTA (1 nM) at 4 and 24 h after injection, ratios of tumor to blood and tumor to nontumor (normal) organ (T/NT) were 8 to 35:1 for all organs or tissue except the spleen, marrow, and kidney, which were between 2:1 and 1:1. Tetravalent (LLP2A-DOTA)(4)-PEG(10,000) (1.1 nM) had tumor uptake similar to the univalent LLP2A-DOTA but higher liver, marrow, and kidney uptake. The excellent T/NT of LLP2A was also demonstrated by small-animal PET with (64)Cu-LLP2A-CB-TE2A at both 4 and 24 h after injection; obvious spleen targeting was apparent, but little kidney or liver activity was observed. Of the conjugates investigated, the univalent, non-PEGylated ligand (111)In-LLP2A-DOTA exhibited the best T/NT ratios and showed the greatest potential for imaging of alpha4beta1 in human lymphoma. Furthermore, this univalent non-PEGylated LLP2A format, as (64)Cu-LLP2A-CB-TE2A, demonstrated excellent tumor targeting by small-animal PET and warrants further investigation as an agent for the study of alpha4beta1 expression in human lymphoid malignancies.

Evaluation of a Novel 18 F-Labeled Positron-Emission Tomography Perfusion Tracer for the Assessment of Myocardial Infarct Size in Rats

Background— The goal of this study was to evaluate a new 18 F-labeled positron-emission tomography (PET) perfusion tracer, 18 F BMS747158-02, for the assessment of myocardial infarct (MI) size. Methods and Results— Wistar rats were studied 24 hours after ligation of the left coronary artery either permanently (n=15) or transiently (n=16) for 30 minutes. Seven nonoperated rats were studied as controls. The rats were injected with 37 MBq of 18 F BMS747158-02 and imaged with a small animal PET scanner for 20 minutes. Polar maps were generated for measurement of PET defect size, and left ventricular systolic and diastolic volumes were assessed in gated images. As a reference, MI size was determined by 2,3,5-triphenyltetrazolium chloride staining of left ventricular tissue samples. Permanent or transient ligation of the left coronary artery produced transmural or subendocardial MI of variable sizes, respectively. In normal rats, PET imaging demonstrated intense and homogeneous uptake of 18 F BMS747158-02 throughout the myocardium. After ligation, sharply defined perfusion defects were present. Throughout the imaging period, the defect size correlated closely with the MI size either after permanent ( r =0.88; P &lt;0.01; mean difference, 1.86%) or transient ( r =0.92; P &lt;0.01; mean difference, 2.16%) ligation of the left coronary artery. Moreover, reduction of left ventricular systolic function measured with PET correlated with the MI size ( r =−0.81; P &lt;0.01; n=23). Conclusions— Myocardial 18 F BMS747158-02 PET imaging provides excellent image quality and uptake properties, enabling accurate evaluation of MI size and left ventricular function in rats. It is a promising technique for evaluation of MI size in clinical trials.

Cascade removal and microPET imaging with 76Br

PET imaging with non-standard nuclides has limitations due to the reduced spatial resolution from the positron range and from the concurrent emission of other gamma rays during the decay process. Particularly in high-resolution small animal PET imaging, these factors become detrimental for accurate quantitation of the activity concentrations from the reconstructed images. This paper presents an evaluation for imaging with such a nuclide, 76Br, through imaging of specifically designed phantoms in a high-resolution small animal PET scanner. A model is presented for the calculation and removal of fortuitous cascade gamma ray coincidences based on estimation of the activity distribution and the attenuation correction file. In this evaluation, it is shown that 2 mm spatial resolution can be achieved with 76Br while 1.7 mm was achieved with 18F using a filtered back projection algorithm despite the much higher end-point energy of the positrons from 76Br. A detailed evaluation of the point spread function for this nuclide was fitted by a double Gaussian function and explained the long tail from the high-energy positrons. These evaluations are crucial for accurate correction for partial volume effects and to provide accurate measurement of the activity concentrations in small animal PET imaging.

Comparative Evaluation of the Translocator Protein Radioligands 11C-DPA-713, 18F-DPA-714, and 11C-PK11195 in a Rat Model of Acute Neuroinflammation

Overexpression of the translocator protein, TSPO (18 kDa), formerly known as the peripheral benzodiazepine receptor, is a hallmark of activation of cells of monocytic lineage (microglia and macrophages) during neuroinflammation. Radiolabeling of TSPO ligands enables the detection of neuroinflammatory lesions by PET. Two new radioligands, (11)C-labeled N,N-diethyl-2-[2-(4-methoxyphenyl)-5,7-dimethylpyrazolo[1,5-alpha]pyrimidin-3-yl]acetamide (DPA-713) and (18)F-labeled N,N-diethyl-2-(2-(4-(2-fluoroethoxy)phenyl)-5,7-dimethylpyrazolo[1,5-alpha]pyrimidin-3-yl)acetamide (DPA-714), both belonging to the pyrazolopyrimidine class, were compared in vivo and in vitro using a rodent model of neuroinflammation. (11)C-DPA-713 and (18)F-DPA-714, as well as the classic radioligand (11)C-labeled (R)-N-methyl-N-(1-methylpropyl)-1-(2-chlorophenyl)isoquinoline-3-carboxamide (PK11195), were used in the same rat model, in which intrastriatal injection of (R,S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolopropionique gave rise to a strong neuroinflammatory response. Comparative endpoints included in vitro autoradiography and in vivo imaging on a dedicated small-animal PET scanner under identical conditions. (11)C-DPA-713 and (18)F-DPA-714 could specifically localize the neuroinflammatory site with a similar signal-to-noise ratio in vitro. In vivo, (18)F-DPA-714 performed better than (11)C-DPA-713 and (11)C-PK11195, with the highest ratio of ipsilateral to contralateral uptake and the highest binding potential. (18)F-DPA-714 appears to be an attractive alternative to (11)C-PK11195 because of its increased bioavailability in brain tissue and its reduced nonspecific binding. Moreover, its labeling with (18)F, the preferred PET isotope for radiopharmaceutical chemistry, favors its dissemination and wide clinical use. (18)F-DPA-714 will be further evaluated in longitudinal studies of neuroinflammatory conditions such as are encountered in stroke or neurodegenerative diseases.

Preliminary study on potential of the jPET-D4 human brain scanner for small animal imaging

One trend in positron emission tomography (PET) instrumentation over the last decade has been the development of scanners dedicated to small animals such as rats and mice. Thicker crystals, which are necessary to obtain higher sensitivity, result in degraded spatial resolution in the peripheral field-of-view (FOV) owing to the parallax error. On the other hand, we are developing the jPET-D4, which is a dedicated human brain PET scanner that has a capability for depth-of-interaction (DOI) measurement. Although its crystal width is about twice that of commercially available small animal PET scanners, we expect the jPET-D4 to have a potential for small animal imaging by making full use of the DOI information. In this article, we investigate the jPET-D4's potential for small animal imaging by comparing it with the microPET Focus220, a state-of-the-art PET scanner dedicated to small animals. The jPET-D4 uses four-layered GSO crystals measuring 2.9 mm x 2.9 mm x 7.5 mm, whereas the microPET Focus220 uses a single layer of LSO crystals measuring 1.5 mm x 1.5 mm x 10.0 mm. First, the absolute sensitivity, counting rate performance and spatial resolution of both scanners were measured. Next a small hot-rod phantom was used to compare their imaging performance. Finally, a rat model with breast tumors was imaged using the jPET-D4. Thanks to the thicker crystals and the longer axial FOV, the jPET-D4 had more than four times higher sensitivity than the microPET Focus220. The noise equivalent counting-rate performance of the jPETD4 reached 1,024 kcps for a rat-size phantom, whereas that of the microPET Focus220 reached only 165 kcps. At the center of the FOV, the resolution was 1.7 mm for the microPET Focus220, whereas it was 3.2 mm for the jPET-D4. On the other hand, the difference of resolution became smaller at the off-center position because the radial resolution degraded faster for the microPET Focus220. The results of phantom imaging showed that the jPET-D4 was comparable to the microPET Focus220 at the off-center position even as the microPET Focus220 outperformed the jPET-D4 except for the peripheral FOV. The jPET-D4 human brain PET scanner, which was designed to achieve not only high resolution but also high sensitivity by measuring DOI information, was proven to have a potential for small animal imaging.

The Chemokine Receptor CXCR4 and the Metalloproteinase MT1-MMP Are Mutually Required during Melanoma Metastasis to Lungs

Melanoma is the most aggressive skin cancer once metastasis begins; therefore, it is important to characterize the molecular players involved in melanoma dissemination. The chemokine receptor CXCR4 and the membrane-bound metalloproteinase MT1-MMP are expressed on melanoma cells and represent candidate molecules for the control of metastasis. Using human melanoma transfectants that either overexpress or silence CXCR4 or MT1-MMP, or that have a combination of overexpression and interference of these proteins, we show that CXCR4 and MT1-MMP coordinate their activities at different steps along melanoma cell metastasis into the lungs. Results from in vivo xenograft mouse models of melanoma lung colonization and mice survival and short-term, homing nested polymerase chain reaction experiments from lung samples indicated that CXCR4 is required at early phases of melanoma cell arrival in the lungs. In contrast, MT1-MMP is not needed for these initial steps but promotes subsequent invasion and dissemination of the tumor with CXCR4. Investigation of potential cross talk between CXCR4 and MT1-MMP revealed that MT1-MMP accumulates intracellularly after melanoma cell stimulation with the CXCR4 ligand CXCL12, and that this process involves the activation of the Rac-Erk1/2 pathway. Subsequent to cell contact with specific basement membrane proteins, MT1-MMP redistributes to the cell membrane in a phosphatidylinositol 3-kinase-dependent manner. These results suggest that combination therapies that target CXCR4 and MT1-MMP should improve the limitations of the current therapies for metastatic melanoma.