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Spectra of 2,2,2-trifluoroethanol and trimethyl phosphate are presented, to demonstrate the potential and limits of heteronuclear J-coupling spectroscopy. This allows one to vary the magnetic field of the low-field nuclear magnetic resonance spectrometer over several octaves.

Purpose: [F]Fluciclatide is an integrin-targeted PET radiopharmaceutical. αβ and αβ are upregulated in tumor angiogenesis as well as on some tumor cell surfaces. Our aim was to use [F]fluciclatide (formerly known as [F]AH111585) for PET imaging of angiogenesis in melanoma and renal tumors and compare with tumor integrin expression. Methods: Eighteen evaluable patients with solid tumors ≥2.0 cm underwent [F]fluciclatide PET/CT. All patients underwent surgery and tumor tissue samples were obtained. Immunohistochemical (IHC) staining with mouse monoclonal antibodies and diaminobenzidine (DAB) was applied to snap-frozen tumor specimens, and additional IHC was done on formalin-fixed paraffin-embedded samples. DAB optical density (OD) data from digitized whole-tissue sections were compared with PET SUV, and Patlak influx rate constant ( K) data, tumor by tumor. Results: Tumors from all 18 patients demonstrated measurable [F]fluciclatide uptake. At the final dynamic time-point (55 min after injection), renal malignancies (in 11 patients) demonstrated an average SUV of 6.4 ± 2.0 (range 3.8 - 10.0), while the average SUV for metastatic melanoma lesions (in 6 patients) was 3.0 ± 2.0 (range 0.7 - 6.5). There was a statistically significant difference in [F]fluciclatide uptake between chromophobe and nonchromophobe renal cell carcinoma (RCCs, with SUV of 8.2 ± 1.8 and 5.4 ± 1.4 ( P = 0.020) and tumor-to-normal kidney (T/N) ratios of 1.5 ± 0.4 and 0.9 ± 0.2, respectively ( P = 0.029). The highest Pearson's correlation coefficients were obtained when comparing Patlak K and αβ OD when segregating the patient population between melanoma and RCC ( r = 0.83 for K vs. melanoma and r = 0.91 for K vs. RCC). SUV showed a moderate correlation with αβ and αβ OD. Conclusion: [F]Fluciclatide PET imaging was well tolerated and demonstrated favorable characteristics for imaging αβ and αβ expression in melanoma and RCC. Higher uptake was observed in chromophobe than in nonchromophobe RCC. [F]Fluciclatide may be a useful radiotracer to improve knowledge of integrin expression. [ABSTRACT FROM AUTHOR]

Purpose: A novel molecular imaging agent has been developed recently, which stains tissues of low extracellular pH [pH (low) insertion peptide, pHLIP]. A pH-dependent process of peptide folding and insertion into cell membranes has been found in vitro. Targeting of acidic solid tumours has been demonstrated in vivo using fluorescence and PET labels. Here, we present proof of feasibility studies of pHLIP with a single-photon emission computed tomography (SPECT) label, Tc-AH114567, with focus on preclinical efficacy and imageability. Procedures: Lewis lung carcinoma, lymph node carcinoma of the prostate and prostate adenocarcinoma tumour xenografts were grown in mice and characterised by the angiogenesis marker Tc-NC100692 and by extracellular pH measurements with P-MRS of 3-aminopropyl phosphonate. Biodistribution was assessed and CT/SPECT imaging performed. Oral administration of bicarbonate served as control. Results and Conclusion: Tc-AH114567 can be obtained via a robust synthesis with good radiolabelling profile and improved formulation. The tracer retains the pH-dependent ability to insert into membranes and to target tumours with similar pharmacokinetics and efficacy that had been demonstrated earlier for pHLIP with optical or Cu PET labels. Despite the inherent challenges of SPECT compared to optical and PET imaging, e.g., in terms of lower sensitivity, Tc-AH114567 shows adequate image quality and contrast. The main development need for transitioning SPECT labelled pHLIP into the clinic is more rapid background signal reduction, which will be the focus of a subsequent optimisation study. [ABSTRACT FROM AUTHOR]

Abstract: 2H solid-state, variable temperature magic angle spinning (MAS) NMR spectra of precipitated samples of the deutero dideuterium complexes Ru(D)2(η2-D2)2(PCy3)2 and RuD(η2-D2)I(PCy3)2 [Cy=cyclohexyl] are presented. They show that even at moderate MAS speed, high resolution is achieved at 7 and 14T allowing 2H chemical shifts and quadrupole couplings to be obtained and assigned to different solid and gaseous 2H species. These two parameters allow identifying chemically different hydrogen species in the material. The analysis of these parameters in this study reveals the presence of three different species in the sample, namely the complexes RuD(η2-D2)I(PCy3)2 and RuD(η2-D2)2I(PCy3)2, and highly mobile HD/D2. These assignments are supported by 2H T 1 relaxation times and 31P MAS NMR spectra. Moreover, variable temperature MAS NMR spectra reveal temperature-dependent line-shape changes, which are clear indications of intramolecular hydrogen exchange of the deutero and the dideuterium ligands and which give an estimate for the activation energy of this process. [Copyright &y& Elsevier]

Abstract: Dynamic Nuclear Polarization (DNP) of the 13C nucleus has been investigated for [1-13C]pyruvic acid, doped with the trityl radical OX063Me, at 4.64T and 1.15K. The dependence of the polarization on microwave frequency, radical concentration and electron saturation was studied. For optimized conditions, a 13C polarization equal to 64±5% was obtained, an increase by more than a factor of two compared with earlier results at 3.35T of the same system. It was furthermore observed that the addition of gadolinium, which resulted in a twofold polarization increase at 3.35T, only resulted in a minor improvement at 4.64T. The dependence of the electron saturation on microwave frequency and microwave power was quantified by first moment measurements which were obtained by nucleus–electron double resonance (NEDOR) experiments. Complete electron saturation was observed for a microwave frequency close to the centre frequency of the ESR line, and by using maximum power of the microwave source. The DNP build-up time at 4.64T (∼3000s) was prolonged by approximately a factor three over the build-up time at 3.35T (∼1200s). However, after approximately 20min of microwave irradiation the polarization at 4.64T exceeded the polarization at 3.35T. [Copyright &y& Elsevier]

Review: 66 refs. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Two 7-fluoroimidazobenzodiazepines (AH114726 and GEH120348), analogs of flumazenil, were labeled with fluorine-18 and evaluated as alternative radioligands for in vivo imaging of the GABAA/benzodiazepine receptor by comparing them to [11C]flumazenil in rhesus monkey. Methods: Radiotracers were prepared from the corresponding nitro-precursors in an automated synthesis module, and primate imaging studies were conducted on a Concorde MicroPET P4 scanner. The brain was imaged for 60 (12×5min frames) or 90min (18×5min frames), and data was reconstructed using the 3D MAP algorithm. Specificity of [18F]AH114726 and [18F]GEH120348 was confirmed by displacement studies using unlabeled flumazenil. Results: [18F]GEH120348 and [18F]AH114726 were obtained in 13–24% yields (end of synthesis) with high chemical (>95%) and radiochemical (>99%) purities, and high specific activities (2061±985Ci/mmol). The in vivo pharmacokinetics of [18F]AH114726 and [18F]GEH120348 were determined in a non-human primate and directly compared with [11C]flumazenil. Both fluorine-18 radioligands showed time-dependent regional brain distributions that correlated with the distribution of [11C]flumazenil and the known concentrations of GABAA/benzodiazepine receptors in the monkey brain. [18F]AH114726 exhibited maximal brain uptake and tissue time-radioactivity curves that were most similar to [11C]flumazenil. In contrast, [18F]GEH120348 showed higher initial brain uptake but very different pharmacokinetics with continued accumulation of radioactivity into the cortical regions of high GABA/benzodiazepine receptor concentrations and very little clearance from the regions of low receptor densities. Rapid washout of both radiotracers occurred upon treatment with unlabeled flumazenil. Conclusion: The ease of the radiochemical synthesis, together with in vivo brain pharmacokinetics most similar to [11C]flumazenil, support that [18F]AH114726 is a suitable option for imaging the GABAA receptor. [Copyright &y& Elsevier]

18 F labeling strategies for unmodified peptides with [ 18 F]fluoride require 18 F-labeled prosthetics for bioconjugation more often with cysteine thiols or lysine amines. Here we explore selective radical chemistry to target aromatic residues applying C-H 18 F-trifluoromethylation. We report a one-step route to [ 18 F]CF 3 SO 2 NH 4 from [ 18 F]fluoride and its application to direct [ 18 F]CF 3 incorporation at tryptophan or tyrosine residues using unmodified peptides as complex as recombinant human insulin. The fully automated radiosynthesis of octreotide[Trp(2-CF 2 18 F)] enables in vivo positron emission tomography imaging.

Purpose: [(18)F]Fluciclatide is an integrin-targeted PET radiopharmaceutical. αvβ3 and αvβ5 are upregulated in tumor angiogenesis as well as on some tumor cell surfaces. Our aim was to use [(18)F]fluciclatide (formerly known as [(18)F]AH111585) for PET imaging of angiogenesis in melanoma and renal tumors and compare with tumor integrin expression., Methods: Eighteen evaluable patients with solid tumors ≥2.0 cm underwent [(18)F]fluciclatide PET/CT. All patients underwent surgery and tumor tissue samples were obtained. Immunohistochemical (IHC) staining with mouse monoclonal antibodies and diaminobenzidine (DAB) was applied to snap-frozen tumor specimens, and additional IHC was done on formalin-fixed paraffin-embedded samples. DAB optical density (OD) data from digitized whole-tissue sections were compared with PET SUV80% max, and Patlak influx rate constant (K i) data, tumor by tumor., Results: Tumors from all 18 patients demonstrated measurable [(18)F]fluciclatide uptake. At the final dynamic time-point (55 min after injection), renal malignancies (in 11 patients) demonstrated an average SUV80% max of 6.4 ± 2.0 (range 3.8 - 10.0), while the average SUV80% max for metastatic melanoma lesions (in 6 patients) was 3.0 ± 2.0 (range 0.7 - 6.5). There was a statistically significant difference in [(18)F]fluciclatide uptake between chromophobe and nonchromophobe renal cell carcinoma (RCCs, with SUV80% max of 8.2 ± 1.8 and 5.4 ± 1.4 (P = 0.020) and tumor-to-normal kidney (T/N) ratios of 1.5 ± 0.4 and 0.9 ± 0.2, respectively (P = 0.029). The highest Pearson's correlation coefficients were obtained when comparing Patlak K i and αvβ5 OD when segregating the patient population between melanoma and RCC (r = 0.83 for K i vs. melanoma and r = 0.91 for K i vs. RCC). SUV80% max showed a moderate correlation with αvβ5 and αvβ3 OD., Conclusion: [(18)F]Fluciclatide PET imaging was well tolerated and demonstrated favorable characteristics for imaging αvβ3 and αvβ5 expression in melanoma and RCC. Higher uptake was observed in chromophobe than in nonchromophobe RCC. [(18)F]Fluciclatide may be a useful radiotracer to improve knowledge of integrin expression.

The rotational spectrum of NSF3 in the ground and v5 = 1 vibrational states has been investigated in the centimeter- and millimeter-wave ranges. R-branch (J + 1 <-- J) transitions for J = 0, 1 and Q-branch rotational transitions for the v5 = 1 vibrational state have been measured by waveguide Fourier transform microwave spectroscopy in the range 8-26.5 GHz. The Q-branch transitions include 28 direct l-type doubling transitions (kl = +1, A1) <--> (kl = +1, A2) with J < or = 62, and 108 direct l-type resonance transitions following the selection rule delta k = delta l = +/-2 with J < or = 60 and G = |k - l| < or = 3. A process called "regional resonance" was observed in which a cluster of levels interacted strongly over a large range in J. This process led to the observation of 55 perturbation-allowed transitions following the selection rules delta(k - l) = +/-3, +/-6. In particular, (kl = +1, A+) <--> (kl = -2, A-), (kl = +4, A+) <--> (kl = +1, A-), (kl = +2) <--> (kl = -1), (kl = +3) <--> (kl = 0), (kl = +2) <--> (kl = -3), and (kl = +3) <--> (kl = -3). The various aspects of the regional resonances are discussed in detail. An accidental near-degeneracy of the kl = 0 and kl = -4 levels at J = 26/27 led to the observation of perturbation-allowed transitions following the selection rule delta(k-l) = +/-6 with (kl = +2) <--> (kl = -4). A corresponding near-degeneracy between kl = -1 and kl = -3 levels at J = 30/31 led to the detection of similar transitions, but with (kl = +3) <--> (kl = -3). In the range 230-480 GHz, R-branch rotational transitions have been measured by absorption spectroscopy up to J = 49 in the ground-state and up to J = 50 in the v5 = 1 vibrational state. The transition frequencies have been analyzed using various reduced forms of the effective Hamiltonians. The data for the v5 = 1 vibrational state have been fitted successfully using two models up to seventh order with delta k = +/-3 interaction parameters constrained (dt constrained to zero, and epsilon to zero or to the ground-state value). On the other hand, reductions with the (delta k = +/-1, deltal = -/+2) interaction parameter q12 fixed to zero failed to reproduce the experimental data since the parameters defining the reduction transformation do not arise in the correct order of magnitude. The ground-state data have been analyzed including parameters up to fourth order constraining either parameters of the delta k = +/-3 interactions to zero (reduction A), or of the delta k = +/-6 interactions to zero (reduction B). The unitary equivalence of the different parameter sets obtained is demonstrated for both vibrational states.

The molecular configuration and crystal structure of solid polycrystalline N,N''-diacetylbiuret (DAB), a potential nitrogen-rich fertilizer, have been analyzed by a combination of solid- and liquid-state NMR spectroscopy, X-ray diffraction, and DFT calculations. Initially a pure NMR study ("NMR crystallography") was performed as available single crystals of DAB were not suitable for X-ray diffraction. Solid-state 13C NMR spectra revealed the unexpected existence of two polymorphic modifications (alpha- and beta-DAB) obtained from different chemical procedures. Several NMR techniques were applied for a thorough characterization of the molecular system, revealing chemical shift anisotropy (CSA) tensors of selected nuclei in the solid state, chemical shifts in the liquid state, and molecular dynamics in the solid state. Dynamic NMR spectroscopy of DAB in solution revealed exchange between two different configurations, which raised the question, is there a correlation between the two different configurations found in solution and the two polymorphic modifications found in the solid state? By using this knowledge, a new crystallization protocol was devised which led to the growth of single crystals suitable for X-ray diffraction. The X-ray data showed that the same symmetric configuration is present in both polymorphic modifications, but the packing patterns in the crystals are different. In both cases hydrogen bonds lead to the formation of planes of DAB molecules. Additional symmetry elements, a two-fold screw in the case of alpha-DAB and a c-glide plane in the case of beta-DAB, lead to a more symmetric (alpha-DAB) or asymmetric (beta-DAB) intermolecular hydrogen-bonding pattern for each molecule.

The molecular configuration and intermolecular arrangement of polycrystalline methoxycarbonylurea (MCU) has been studied by a combination of chemical editing, rotational echo double resonance (REDOR) spectroscopy and ab initio calculations. From the multispin IS(n) REDOR experiments several dipolar couplings were determined and converted into distance constraints. Intra- and intermolecular dipolar couplings were distinguished by isotope dilution. The configuration of the MCU molecule can be determined from three torsion angles Psi1, Psi2, and Psi3. Ab initio calculations showed that these angles are either 0 degrees or 180 degrees (Z or E). From the REDOR experiments, the E configuration was found for Psi1 and Psi2 and the Z configuration for Psi3. Thus the configuration of MCU in the solid state was determined to be EEZ. Distance constraints for the intermolecular arrangement of MCU were obtained by performing REDOR experiments on 13C15N2 MCU with different degrees of isotope dilution and on a cocrystallized 1:1 mixture of 13C(urea) MCU and 15N(amide) MCU. By combining these distance constraints with molecular modeling, three different possible packing motifs for MCU molecules were found. The molecules in these motifs are arranged as linear chains with methoxy groups at the borders of the chains. All the intermolecular hydrogen bond donors and acceptors in the interior of the chain are saturated.