The MINOS CollaborationArgonne -Athens -Caltech -Chicago -Dubna -Fermilab -Harvard IHEP-Beijing -Indiana -ITEP-Moscow -Lebedev Livermore VCL-London Minnesota -Oxford -Pittsburgh -Protvino -Rutherford -Stanford -SussexTexas A&M -Texas-Austin -Tufts -Western Washington - Executive summaryThe MINOS (Main Injector Neutrino Oscillation Search) experiment is designed to search for neutrino oscillations with a sensitivity significantly greater than has been achieved to date. The phenomenon of neutrino oscillations, whose existence has not been proven convincingly so far, allows neutrinos of one "flavor" (type) to slowly transform themselves into another flavor, and then back again to the original flavor, as they propagate through space or matter.The MINOS experiment is optimized to explore the region of neutrino oscillation "para meter space" (values of the !:l.m 2 and sin 2 29 parameters) suggested by previous investigations of atmospheric neutrinos: the Kamiokande, 1MB, Super-Kamiokande and Soudan 2 experi ments. The study of oscillations in this region with a neutrino beam from the Main Injector requires measurements of the beam after a very long flight path. This in turn requires an intense neutrino beam and a massive detector in order to have an adequate event rate at a great distance from the source.We propose to enhance significantly the physics capabilities of the MINOS experiment by the addition of a Hybrid Emulsion Detector at Soudan, capable of unambigous identification of the neutrino flavor. Recent developments in emulsion experiments make such a detector possible, although significant technological challenges must be overcome. We propose to initiate an R&D effort to identify major potential problems and to develop practical solutions to them.In addition to this primary motivation for this R&D work, we note that the strong and growing interest in studies of neutrino oscillations using neutrino beams from future muon storage rings provides another potential application. These beams will offer significantly higher intensities, albeit of mixed 1I1J-and lie, beams. In order to take full advantage of these beams for neutrino oscillation studies it will be necessary that the detector be capable of determination of the flavor of the final state lepton, and the lepton's charge in a significant fraction of the interactions. At present, an emulsion detector in an external magnetic field appears best suited to offer such capabilities. The R&D effort discussed here will be an important step towards a design of such a future detector. This document is organized as follows:• Chapter 1 summarizes the physics motivation for the proposed emulsion detector,• Chapter 2 briefly reviews the status of the emulsion technology and its aplication to particle physics experiments,• Chapter 3 discusses design considerations for an emulsion detector,• Chapter 4 describes some of the details of a possible detector as well as results from the work up to date,• Chapter 5 outlines the proposed R&D program and summarizes the resources req...

A europium(III) DO3A-tris(amide) complex is reported for imaging pH by MRI using ratiometric CEST principles. Deprotonation of a single phenolic proton between pH 6 and 7.6 results in an ~5 ppm shift in the water exchange CEST peak that is easily detected by MRI. Collection of two CEST images at two slightly different activation frequencies provides a direct readout of solution pH without the need of a concentration marker.Magnetic resonance imaging (MRI) is one of the most widely used, noninvasive imaging modalities in clinical medicine.1 One reason for its popularity is that image contrast arises from inherent differences in water proton densities and relaxation rates between various tissue components. Even with these natural contrast differences between tissues, exogenous contrast agents that alter proton relaxation times (T 1 , T 2 , or T 2 *) are still widely used to enhance contrast between various tissue compartments.2 A new type of image contrast based on a chemical exchange saturation transfer (CEST) mechanism was recently introduced.3 Paramagnetic versions of CEST agents have the potential of offering two major advantages over Gd 3+ -based imaging agents.4 First, image contrast produced by a PARACEST agent can be switched "on" or "off" by application of a frequency-selective radio frequency pulse. This feature allows potential multiplexing of agents in a single study. Second, since contrast in these systems is based on chemical exchange of either liable protons or water molecules, the agents are extremely sensitive to exchange rates (k ex ). This feature makes them attractive for developing biologically responsive sensors. PARACEST sensors using a variety of design platforms have been reported for measuring pH,5 , 6 temperature,7 Zn 2+, 8 glucose,9 nitric oxide,10 phosphate esters,11 and enzyme activity.12 , 13 Most PARACEST sensors reported to date have a CEST signal that changes intensity in response to external stimuli. This of course requires a separate measure of agent concentration to obtain quantitative results. Some exceptions include agents that use either a cocktail of agents5 or single agents having multiple weakly shifted −NH exchangeable protons for ratiometric imaging.6 The later design feature has the disadvantage of relying on exchange sites that are relatively close to the bulk water frequency (typically < 15 ppm). Here, we address this problem by presenting a novel europium(III) DOTAmonoketonetris(amide) complex that has a single highly shifted water exchange peak whose frequency varies as a function of solution pH. We demonstrate that this single agent is nearly ideal for measuring pH by use of ratiometric CEST imaging without the need of a second concentration marker.Previously reported Eu 3+ -based PARACEST agents have a highly shifted water exchange peak that is independent of pH between 5 and 8.5 More recently, we discovered that the chemical shift of the Eu 3+ -bound water exchange peak can be altered considerably by varying the electron density on a single amide oxygen ...

Modulation of water exchange in lanthanide(III)-DOTA type complexes has drawn considerable attention over the past two decades particularly because of their application as contrast agents for Magnetic Resonance Imaging (MRI). LnDOTA-tetraamide complexes display unusually slow water exchange kinetics and this chemical property offers an opportunity to use these complexes as a new type of contrast agent based upon the chemical exchange saturation transfer (CEST) mechanism. Six new DOTA-tetraamide ligands having side-chain amide arms with varying hydrophobicity and polarity were prepared and the water exchange characteristic of complexes formed with europium(III) complexes were investigated. The results show that introduction of steric bulk into the amide side-chain arms of the europium(III) complexes not only favors formation of the mono-capped twisted square antiprism (TSAP) coordination isomers, the isomer that is generally less favourable for CEST, but also accelerates water exchange in the mono-capped square antiprism (SAP) isomers. However, converting single methyl groups on these bulky arms to carboxyl or carboxyl ethyl esters results in a rather dramatic decrease in water exchange rates, about 50-fold. Thus, steric bulk, polarity, hydrophobicity of the amide side-chains, each contribute to organization of water molecules in the second hydration sphere of the europium(III) ion and this in turn controls water exchange in these complexes.

VNC images derived from novel dual layer spectral detector CT demonstrate attenuation values similar to unenhanced images in all tissues evaluated except for subcutaneous fat. Further study is needed to determine if attenuation thresholds currently used clinically for common pathology should be adjusted, particularly for lesions containing fat.

Eine Serie von Nanosonden für die Kernspintomographie wurde aus ionisierbaren Diblockcopolymeren hergestellt und mit verschiedenen 19F‐Rezeptoren für spezifische pH‐Änderungen kodiert. Das pH‐Signal ist extrem scharf (ΔpHAn/Aus≈0.25 pH) und resultiert aus der Dissoziation der Polymermicellen (siehe Schema). Ein System aus drei Nanosonden ermöglichte die qualitative Messung von Umgebungs‐pH‐Werten.

Imaging all the people: Using ionizable diblock copolymers a series of nanoprobes encoded with different 19F reporters for specific pH transitions is prepared for use in MRI. The pH response of the nanoprobes is extremely sharp (ΔpHON/OFF≈0.25 pH), and results from the disassembly of polymer micelles (see scheme). A collection of three nanoprobes provides the proof of concept and allows for a qualitative measurement of environmental pH values.

Linear polymers of PARACEST agents were prepared by using classical free radical chain polymerization conditions. The Eu 3+ -polymers exhibited similar intermediate-to-slow water exchange and CEST characteristics as the Eu 3+ -monomers. This provided an avenue to lower the detection limit of these imaging agents substantially and makes them potentially useful as MRI sensors for molecular imaging.Magnetic resonance imaging (MRI) is an important clinical tool for anatomical imaging and monitoring certain tissue characteristics, such as perfusion and diffusion. Although MRI contrast agents are often used to improve diagnostic specificity, MRI is limited in molecular imaging applications because of its inherently low sensitivity when compared to nuclear medicine or fluorescence imaging. 1 Consequently, the search for new agents that can be detected by MRI at much lower concentrations continues to be an active area of research. The most widely used contrast agents are low molecular weight Gd 3+ -based complexes that shorten A new mechanism for generating image contrast, chemical exchange saturation transfer or CEST, 6 is of interest for targeted imaging applications. One intriguing aspect of CEST is that the effect can be switched on and off depending on whether a frequency selective pre-saturation pulse is applied or not. This feature, not available with Gd 3+ agents because they are always on, allows acquisition of pre-and post-contrast images to be acquired nearly simultaneously. Paramagnetic CEST (PARACEST) agents with chemical exchange groups shifted well away from the bulk water signal offer significant advantages over diamagnetic CEST agents in that faster exchange systems are operable. 7 Theory shows that the detection limit of a single PARACEST exchanging species with an optimal water exchange rate, chemical shift, and relaxation properties is comparable to a single Gd 3+ -based T 1 agent. 7 However, molecular imaging often requires the detection of targets that are present in concentrations too low to be detected by an agent with a single paramagnetic center so finding ways to maximize the number of PARACEST exchanging species at a targeted site is an important goal for MRI to complete in the field of molecular imaging. Van Zijl and coworkers first demonstrated this in various diamagnetic polymers, such as polyamino acids and even single-stranded RNA. 8 This stimulated us to consider polymeric PARACEST agents prepared by a simple free-radical chain polymerization reaction as a way to lower the detection limit of such agents.Ligand 1 (prepared as described in supplementary materials) was polymerized using either 2%, 5% or 10% (w/w) azo-bis(4-cyanovaleric acid) as initiator in H 2 O at 70°C to afford water soluble, linear polymers differing in size only. After 48 hr, the products were purified by dialysis using a 3kD MW cut-off membrane and the weight-average molecular weight (M w ) and number-average molecular weight (M n ) of each poly1 was determined by light scattering GPC (Table 1). All three pol...

A novel approach for the design of responsive paramagnetic chemical exchange saturation transfer (PARACEST) magnetic resonance imaging (MRI) agents has been developed where the signal is “turned on” by altering the longitudinal relaxation time (T1) of bulk water protons. To demonstrate this approach, a model Eu(DOTA-tetraamide) complex (DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) containing two nitroxide free radical units was synthesized. The nitroxide groups substantially shortened the T1 of the bulk water protons which, in turn, resulted in quenching of the CEST signal. Reduction of paramagnetic nitroxide moieties to a diamagnetic species resulted in the appearance of CEST. The modulation of CEST by T1 relaxation provides a new platform for designing biologically responsive MRI agents.