100-mJ, 100-W cryogenically cooled Yb:YLF laser.

We present a diode-pumped Yb:YLF laser system generating 100-mJ sub-ps pulses at a 1-kHz repetition rate (100 W average power) by chirped-pulse amplification. The laser consists of a cryogenically cooled 78 K, regenerative, eight-pass booster amplifier seeded by an all-fiber front end. The output pulses are compressed to 980 fs in a single-grating Treacy compressor with a throughput of 89%. The laser will be applied to multi-cycle THz generation and pumping of high average power parametric amplifiers.

Free-electron laser temporal diagnostic beamline FL21 at FLASH.

A beamline for temporal diagnostics of extreme ultraviolet (XUV) femtosecond pulses at the free-electron laser in Hamburg (FLASH) at DESY was designed, built and put into operation. The intense ultra-short XUV pulses of FLASH fluctuate from pulse to pulse due to the underlying FEL operating principle and demand single-shot diagnostics. To cope with this, the new beamline is equipped with a terahertz field-driven streaking setup that enables the determination of single pulse duration and arrival time. The parameters of the beamline and the diagnostic setup as well as some first experimental results will be presented. In addition, concepts for parasitic operation are investigated.

Development of the High-Affinity Carborane-Based Cannabinoid Receptor Type 2 PET Ligand [18F]LUZ5-d8.

The development of cannabinoid receptor type 2 (CB2R) radioligands for positron emission tomography (PET) imaging was intensively explored. To overcome the low metabolic stability and simultaneously increase the binding affinity of known CB2R radioligands, a carborane moiety was used as a bioisostere. Here we report the synthesis and characterization of carborane-based 1,8-naphthyridinones and thiazoles as novel CB2R ligands. All tested compounds showed low nanomolar CB2R affinity, with (Z)-N-[3-(4-fluorobutyl)-4,5-dimethylthiazole-2(3H)-ylidene]-(1,7-dicarba-closo-dodecaboranyl)-carboxamide (LUZ5) exhibiting the highest affinity (0.8 nM). Compound [18F]LUZ5-d8 was obtained with an automated radiosynthesizer in high radiochemical yield and purity. In vivo evaluation revealed the improved metabolic stability of [18F]LUZ5-d8 compared to that of [18F]JHU94620. PET experiments in rats revealed high uptake in spleen and low uptake in brain. Thus, the introduction of a carborane moiety is an appropriate tool for modifying literature-known CB2R ligands and gaining access to a new class of high-affinity CB2R ligands, while the in vivo pharmacology still needs to be addressed.

Continuous-wave Tm:YLF laser with ultrabroad tuning (1772-2145 nm).

We report detailed experimental data aiming for rigorous investigation of Tm:YLF laser performance, especially with a focus on tuning behavior. Continuous-wave (cw) lasing performance of Tm:YLF crystals with thulium dopings in the 2-6% range is investigated under diode and Ti:Sapphire pumping at 792 nm and 780 nm, respectively. While employing the c-axis, we have achieved cw lasing thresholds below 20 mW, laser output power up to 1.42 W, and laser slope efficiencies as high as 70% with respect to absorbed pump power. The passive loss of the Tm:YLF crystal is estimated to be as low as 0.05% per cm, corresponding to a crystal figure of merit above 10000. Via employing this low-loss crystal and a 2-mm thick off-surface optical axis birefringent filter (BRF) with strong sideband rejection, a record cw tuning range covering the 1772-2145 nm interval is demonstrated (except a small gap between 1801-1815nm region). Detailed lifetime and emission cross section measurements have been performed to explain the observed performance, and strategies for further performance enhancement are discussed.

Broadly tunable (993-1110 nm) Yb:YLF laser.

We have investigated room-temperature continuous-wave (cw) lasing performance of Yb:YLF oscillators in detail using rod-type crystals with low Yb-doping (2%). The laser is pumped by a low-cost, high brightness, 10 W, 960 nm single-emitter multimode diode. Laser performance is acquired in both E//a and E//c configurations, using 12 different output couplers with transmission ranging from 0.015% to 70%. We have estimated the passive loss of the Yb:YLF crystal as 0.06% per cm, corresponding to an impressive crystal figure of merit above 4000. The low-doping level not only reduces the system losses but also minimizes the thermal load as the low doped crystals enable distribution of heat load in a greater volume. Using the advantages of lower loss and improved thermal behavior, we have achieved cw output power above 4 W, cw slope efficiencies up to 78%, and a record cw tuning range covering the 993-1110 nm region (117 nm). The output power performance achieved in this initial work is limited by the available pump power, and future room-temperature Yb:YLF systems have the potential to produce higher output power levels.

Synthesis and In Vitro Evaluation of a Set of 6-Deoxy-6-thio-carboranyl d-Glucoconjugates Shed Light on the Substrate Specificity of the GLUT1 Transporter.

Glucose- and sodium-dependent glucose transporters (GLUTs and SGLTs) play vital roles in human biology. Of the 14 GLUTs and 12 SGLTs, the GLUT1 transporter has gained the most widespread recognition because GLUT1 is overexpressed in several cancers and is a clinically valid therapeutic target. We have been pursuing a GLUT1-targeting approach in boron neutron capture therapy (BNCT). Here, we report on surprising findings encountered with a set of 6-deoxy-6-thio-carboranyl d-glucoconjugates. In more detail, we show that even subtle structural changes in the carborane cluster, and the linker, may significantly reduce the delivery capacity of GLUT1-based boron carriers. In addition to providing new insights on the substrate specificity of this important transporter, we reach a fresh perspective on the boundaries within which a GLUT1-targeting approach in BNCT can be further refined.

Semiconductor saturable absorber mirror mode-locked Yb:YLF laser with pulses of 40 fs.

We have generated pulses as short as 40 fs with an average power of 265 mW from a semiconductor saturable absorber mirror (SESAM) mode-locked Yb:YLF oscillator employing a 1% transmitting output coupler (OC). The room-temperature laser is pumped by a low-cost 960 nm single-emitter multimode diode and dispersion compensation is provided via double chirped mirrors (DCMs). The 40-fs pulses are centered around 1050 nm with a width of 34 nm at a repetition rate of 87.3 MHz. By increasing the output coupling to 5% and by using Gires-Tournois interferometer (GTI) mirrors for dispersion compensation, we have also demonstrated 380-fs pulses with 1.85 W of average power around 1025 nm at a repetition rate of 190.4 MHz. Using an intracavity off-surface optic axis birefringent filter, the central wavelength of the pulses could be tuned in the 1020-1025 nm and 1019-1047 nm ranges for the 5% and 1% transmitting OCs, respectively. To the best of our knowledge, these are the shortest pulses and highest average and peak powers generated from room-temperature Yb:YLF lasers to date.

Mode-locked Cr:LiSAF laser far off the gain peak: tunable sub-200-fs pulses near 1 µm.

We report, to the best of our knowledge, the first mode-locking results of a Cr:LiSAF laser near the 1 µm region. The system is pumped only by a single 1.1 W high-brightness tapered diode laser at 675 nm. A semiconductor saturable absorber mirror (SESAM) with a modulation depth of 1.5% and non-saturable losses below 0.5% was used for mode-locking. Once mode-locked, the Cr:LiSAF laser produced almost-transform-limited sub-200-fs pulses with up to 12.5 mW of average power at a repetition rate of 150 MHz. Using an intracavity birefringent filter, the central wavelength of the pulses could be smoothly tuned in the 1000-1020 nm range. Via careful dispersion optimization, pulse widths could be reduced down to the 110-fs level. The performance in this initial study was limited by the design parameters of the SESAM used, especially its passive losses and could be improved with an optimized SESAM design.

Highly efficient cryogenic Yb:YLF regenerative amplifier with 250 W average power.

We report an efficient diode-pumped high-power cryogenic regenerative amplifier operating at 1019 nm employing the c axis of Yb:YLF. Compared to the usually selected 1017 nm transition of the a axis, the c-axis 1019 nm line has a three-fold higher emission cross section and still possesses a full-width at half-maximum (FWHM) of 6.5 nm at 125 K. The chirped-pulse amplifier system is seeded by a fiber front-end with energy of 30 nJ and a stretched pulse width of 2 ns. In regenerative amplification studies, using the advantage of higher gain in the c axis, we have achieved record average powers up to 370 W with an extraction efficiency of 78% at a 50 kHz repetition rate. The output pulses were centered on 1019.15 nm with a FWHM bandwidth of 1.25 nm, which supports sub-1.5 ps pulse durations. The output beam maintained a TEM00 beam profile at output power levels below 250 W with an M2 below 1.2. Above this power level, the thermally induced lensing in Yb:YLF created a multimode output beam. The thermal lens was rather dynamic and deteriorated the system stability above a 250 W average power level.

High power (>500W) cryogenically cooled Yb:YLF cw-oscillator operating at 995†nm and 1019†nm using E//c axis for lasing.

We present record continuous wave (cw) output power levels from cryogenically cooled Yb:YLiF4 (Yb:YLF) lasers in rod geometry. The laser system is pumped by a state-of-the-art 960 nm diode module, and vertically polarized lasing was employed using the E//c axis of Yb:YLF. Lasing performance was investigated at different output coupling levels in different cavity configurations and the laser crystal temperature was estimated via monitoring the emission spectrum of the gain media. We have obtained a cw output power up to 400 W at a wavelength of 995 nm. The absorbed pump power was around 720 W, and the laser output had a TEM00 beam profile with an M2 of 1.3 in both axes. At higher absorbed pump power levels with increasing laser crystal temperature, we observed a lasing wavelength shift from 995 nm to 1019 nm. In this regime cw output power levels above 500 W have been achieved at an absorbed pump power of 750 W. Further power scaling was limited by the onset of strong thermal lensing. We discuss underlying physical mechanisms for the wavelength shift and present detailed temperature measurements under lasing conditions.

Theranostics in Boron Neutron Capture Therapy.

Boron neutron capture therapy (BNCT) has the potential to specifically destroy tumor cells without damaging the tissues infiltrated by the tumor. BNCT is a binary treatment method based on the combination of two agents that have no effect when applied individually: 10B and thermal neutrons. Exclusively, the combination of both produces an effect, whose extent depends on the amount of 10B in the tumor but also on the organs at risk. It is not yet possible to determine the 10B concentration in a specific tissue using non-invasive methods. At present, it is only possible to measure the 10B concentration in blood and to estimate the boron concentration in tissues based on the assumption that there is a fixed uptake of 10B from the blood into tissues. On this imprecise assumption, BNCT can hardly be developed further. A therapeutic approach, combining the boron carrier for therapeutic purposes with an imaging tool, might allow us to determine the 10B concentration in a specific tissue using a non-invasive method. This review provides an overview of the current clinical protocols and preclinical experiments and results on how innovative drug development for boron delivery systems can also incorporate concurrent imaging. The last section focuses on the importance of proteomics for further optimization of BNCT, a highly precise and personalized therapeutic approach.

Modular Synthetic Approach to Carboranyl‒Biomolecules Conjugates.

The development of novel, tumor-selective and boron-rich compounds as potential agents for use in boron neutron capture therapy (BNCT) represents a very important field in cancer treatment by radiation therapy. Here, we report the design and synthesis of two promising compounds that combine meta-carborane, a water-soluble monosaccharide and a linking unit, namely glycine or ethylenediamine, for facile coupling with various tumor-selective biomolecules bearing a free amino or carboxylic acid group. In this work, coupling experiments with two selected biomolecules, a coumarin derivative and folic acid, were included. The task of every component in this approach was carefully chosen: the carborane moiety supplies ten boron atoms, which is a tenfold increase in boron content compared to the l-boronophenylalanine (l-BPA) presently used in BNCT; the sugar moiety compensates for the hydrophobic character of the carborane; the linking unit, depending on the chosen biomolecule, acts as the connection between the tumor-selective component and the boron-rich moiety; and the respective tumor-selective biomolecule provides the necessary selectivity. This approach makes it possible to develop a modular and feasible strategy for the synthesis of readily obtainable boron-rich agents with optimized properties for potential applications in BNCT.

Ruthenacarborane-Phenanthroline Derivatives as Potential Metallodrugs.

Ruthenium-based complexes have received much interest as potential metallodrugs. In this work, four RuII complexes bearing a dicarbollide moiety, a carbonyl ligand, and a phenanthroline-based ligand were synthesized and characterized, including single crystal diffraction analysis of compounds 2, 4, and 5 and an observed side product SP1. Complexes 2-5 are air and moisture stable under ambient conditions. They show excellent solubility in organic solvents, but low solubility in water.

High-power passively mode-locked cryogenic Yb:YLF laser.

We report, to the best of our knowledge, the first mode-locked operation of Yb:YLF gain media at cryogenic temperatures. A saturable Bragg reflector was used for initiating and sustaining mode locking. Once aligned, the system was self-starting and quite robust. Using output couplers in the 10-40% range, 3-5 ps long pulses with an average power as high as 28 W were achieved. The repetition rate was 46.45 MHz, and the corresponding pulse energy and peak power were as high as 602 nJ and 126.5 kW, respectively. The central wavelength of the mode-locked pulses could be tuned in the 1013.5-1019 nm range using an intracavity birefringent filter. The achieved output power performance is two to three orders of magnitude higher than previous room-temperature Yb:YLF systems.

Selective Neuropeptide Y Conjugates with Maximized Carborane Loading as Promising Boron Delivery Agents for Boron Neutron Capture Therapy.

G-protein-coupled receptors like the human Y1 receptor (hY1R) are promising targets in cancer therapy due to their high overexpression on cancer cells and their ability to internalize together with the bound ligand. This mechanism was exploited to shuttle boron atoms into cancer cells for the application of boron neutron capture therapy (BNCT), a noninvasive approach to eliminate cancer cells. A maximized number of carboranes was introduced to the hY1R-preferring ligand [F7,P34]-NPY by solid phase peptide synthesis. Branched conjugates loaded with up to 80 boron atoms per peptide molecule exhibited a maintained receptor activation profile, and the selective uptake into hY1R-expressing cells was demonstrated by internalization studies. In order to ensure appropriate solubility in aqueous solution, we proved the need for eight hydroxyl groups per carborane. Thus, we suggest the utilization of bis-deoxygalactosyl-carborane building blocks in solid phase peptide synthesis to produce selective boron delivery agents for BNCT.

A Selective Carborane-Functionalized Gastrin-Releasing Peptide Receptor Agonist as Boron Delivery Agent for Boron Neutron Capture Therapy.

Boron neutron capture therapy (BNCT) allows the selective elimination of malignant tumor cells without affecting healthy tissue. Although this binary radiotherapy approach has been known for decades, BNCT failed to reach the daily clinics to date. One of the reasons is the lack of selective boron delivery agents. Using boron loaded peptide conjugates, which address G protein-coupled receptors overexpressed on tumor cells allow the intracellular accumulation of boron. The gastrin-releasing peptide receptor (GRPR) is a well-known target in cancer diagnosis and can potentially be used for BNCT. Here, we present the successful introduction of multiple bis-deoxygalactosyl-carborane building blocks to the GRPR-selective ligand [d-Phe6, ß-Ala11, Ala13, Nle14]Bn(6-14) (sBB2L) generating peptide conjugates with up to 80 boron atoms per molecule. Receptor activation was retained, metabolic stability was increased, and uptake into PC3 cells was proven without showing any intrinsic cytotoxicity. Furthermore, undesired uptake into liver cells was suppressed by using l-deoxygalactosyl modified carborane building blocks. Due to its high boron loading and excellent GRPR selectivity, this conjugate can be considered as a promising boron delivery agent for BNCT.

Tuning a modular system - synthesis and characterisation of a boron-rich s-triazine-based carboxylic acid and amine bearing a galactopyranosyl moiety.

Introduction of a bis(isopropylidene)-protected galactopyranosyl moiety in s-triazine-based boron-rich carboxylic acids and amines results in soluble and suitable coupling partners for tumour-selective biomolecules with applications as selective agents for boron neutron capture therapy (BNCT). Bearing either a carboxylic acid or primary amine as a functional group, these compounds are highly versatile and thus largely extend the possible coupling strategies with suitable biomolecules. Modification of the gastrin-releasing peptide receptor (GRPR) selective agonist [d-Phe6, ß-Ala11, Ala13, Nle14]Bn(6-14) with the carboxylic acid derivative yielded a bioconjugate with an optimal receptor activation and internalisation profile. This demonstrates the great potential of this approach for the development of novel boron delivery agents.

Enlargement of a Modular System-Synthesis and Characterization of an s-Triazine-Based Carboxylic Acid Ester Bearing a Galactopyranosyl Moiety and an Enormous Boron Load.

The amount of boron accumulated in tumor tissue plays an important role regarding the success of the boron neutron capture therapy (BNCT). In this article, we report a modular system, combining readily available starting materials, like glycine, 1,3,5-triazine and the well-known 9-mercapto-1,7-dicarba-closo-dodecaborane(12), as well as α-d-galactopyranose for increased hydrophilicity, with a novel boron-rich tris-meta-carboranyl thiol.

Modular triazine-based carborane-containing carboxylic acids - synthesis and characterisation of potential boron neutron capture therapy agents made of readily accessible building blocks.

Based on a modular combination of s-triazine, the well-known 9-mercapto-1,7-dicarba-closo-dodecaborane(12) and commercially available carboxylic acids, namely thioglycolic acid, glycine, and Nα-Boc-l-lysine, several carboxylic acid derivatives were synthesised and fully characterised. The thioglycolic acid derivative was introduced into a peptide hormone by solid phase peptide synthesis. High activity and selective internalisation into peptide receptor-expressing cells was observed. With a very high boron content of twenty boron atoms, these derivatives are interesting as selective Boron Neutron Capture Therapy (BNCT) agents.

Pump-probe laser system at the FXE and SPB/SFX instruments of the European X-ray Free-Electron Laser Facility.

User operation at the European X-ray Free-Electron Laser Facility started at the SASE1 undulator beamline in fall 2017. The majority of the experiments utilize optical lasers (mostly ultrafast) for pump-probe-type measurements in combination with X-ray pulses. This manuscript describes the purpose-developed pump-probe laser system as installed at SASE1, implemented features and plans for further upgrades.