Hyperpolarization can increase the sensitivity of NMR/MRI experiments but the primary limitation is the T 1 decay of magnetization. Due to its long T 1 , hyperpolarized 89 Y nucleus makes an excellent candidate as an in vivo spectroscopy/imaging probe. Here we report the 89 Y chemical shift dependence upon pH for two hyperpolarized 89 Y(III) complexes and demonstrate how such complexes can be used as sensitive spectroscopy/imaging agents to measure pH.Dynamic nuclear polarization (DNP) of a NMR sample can significantly increase sensitivity by creating nuclear spin polarization levels that are much higher than ambient temperature Boltzman levels. DNP is based on the transfer of electron spin polarization from a stable free radical to coupled nuclear spins by microwave irradiation in a frozen glass matrix at low temperatures (around 1K). The method gained practical importance when it was demonstrated that compounds hyperpolarized in the solid state could be dissolved and transferred into an NMR magnet for spectrum acquisition with negligible loss of polarization. 1 Liquid state DNP NMR offers dramatic signal enhancements, 10,000-fold or more, for some 13 C and 15 N enriched compounds. Such increases in sensitivity have made it possible to perform molecular/ functional imaging of nuclei other than 1H. Hyperpolarized 13 C labeled substrates, particularly [1-13 C]-pyruvate, have successfully been used to study metabolism in various normal and diseased tissues. 2 While the advantages of 13 C labeled metabolites as imaging agents are obvious, the typical longitudinal relaxation time (T 1 ) of 13 C nuclei (few seconds to ∼1 minute) limits the metabolic processes that can be studied by hyperpolarized 13 C compounds. The time constraint emerging from the inevitable decay of polarization motivates the search for long T 1 agents. Among the NMR active nuclei, 89 Y in its diamagnetic 3+ oxidation state has one of the longest T 1 relaxation times known (600 s or longer). 3 This very long T 1 combined with a favorable spin quantum number (1/2), sharp NMR line width (3)(4)(5) Because of the combined effects of a low γ, low sensitivity and long T 1 , acquiring 89 Y NMR data on thermally polarized samples is impractical, often requiring days even for concentrated solutions. Our preliminary experiments have shown that various chelated forms of Y(III) including YDOTP can be polarized with currently available commercial hardware using the trityl radical (OX63) as a polarizing agent. 3 While only a modest signal enhancement was observed previously for YDOTP (298-fold over thermal equilibrium at 310 K), we are now able to routinely achieve much higher enhancements (∼3000-fold) by optimizing the sample preparation prior to DNP (see Supporting Information).The 89 Y chemical shift of hyperpolarized 89 YDOTP as a function of pH is shown in Figure 2. Given the long T 1 of YDOTP, the entire 89 Y chemical shift versus pH dataset was collected using a single batch of hyperpolarized YDOTP in about 3 min. In comparison, collecting this ...

A bifunctional version of PCTA (3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-3,6,9,-triacetic acid) that exhibits fast complexation kinetics with the trivalent lanthanide(III) ions was synthesized in reasonable yields starting from N, N′, N″-tristosyl-(S)-2-(p-nitrobenzyl)-diethylenetriamine. pH-potentiometric studies showed that the basicities of p-nitrobenzyl-PCTA and the parent ligand PCTA were similar. The stability of M(NO 2 -Bn-PCTA) (M = Mg 2+ , Ca 2+ , Cu 2+ , Zn 2+ ) complexes was similar to that of the corresponding PCTA complexes while the stability of Ln 3+ complexes of the bifunctional ligand is somewhat lower than that of PCTA chelates. The rate of complex formation of Ln(NO 2 -Bn-PCTA) complexes was found to be quite similar to that of PCTA, a ligand known to exhibit the fastest formation rates among all lanthanide macrocyclic ligand complexes studied to date. The acid catalyzed decomplexation kinetic studies of the selected Ln (NO 2 -Bn-PCTA) complexes showed that the kinetic inertness of the complexes was comparable to that of Ln(DOTA) chelates making the bifunctional ligand NO 2 -Bn-PCTA suitable for labeling biological vectors with radioisotopes for nuclear medicine applications.

Lanthanide complexes (Eu(3+), Gd(3+) and Yb(3+)) of two different 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid tetraamide derivatives containing two (2) and four (3) O-benzyl-L-serine amide substituents were synthesized and their chemical exchange saturation transfer (CEST) and relaxometric properties were examined in the presence and absence of human serum albumin (HSA). Both Eu2 and Eu3 display a significant CEST effect from a single slowly exchanging Eu(3+)-bound water molecule, making these PARACEST complexes potentially useful as vascular MRI agents. Yb2 also showed a detectable CEST effect from both the Yb(3+)-bound water protons and the exchangeable NH amide protons, making it potentially useful as a vascular pH sensor. Fluorescence displacement studies using reporter molecules indicate that both Gd2 and Gd3 displace dansylsarcosine from site II of HSA with inhibition constants of 32 and 96 microM, respectively, but neither complex significantly displaces warfarin from site I. Water proton relaxation enhancements of 135 and 171% were observed upon binding of Gd2 and Gd3 to HSA, respectively, at 298 K and pH 7.4.