Metallaphotoredox aryl and alkyl radiomethylation for PET ligand discovery.

Positron emission tomography (PET) radioligands (radioactively labelled tracer compounds) are extremely useful for in vivo characterization of central nervous system drug candidates, neurodegenerative diseases and numerous oncology targets1. Both tritium and carbon-11 radioisotopologues are generally necessary for in vitro and in vivo characterization of radioligands2, yet there exist few radiolabelling protocols for the synthesis of either, inhibiting the development of PET radioligands. The synthesis of such radioligands also needs to be very rapid owing to the short half-life of carbon-11. Here we report a versatile and rapid metallaphotoredox-catalysed method for late-stage installation of both tritium and carbon-11 into the desired compounds via methylation of pharmaceutical precursors bearing aryl and alkyl bromides. Methyl groups are among the most prevalent structural elements found in bioactive molecules, and so this synthetic approach simplifies the discovery of radioligands. To demonstrate the breadth of applicability of this technique, we perform rapid synthesis of 20 tritiated and 10 carbon-11-labelled complex pharmaceuticals and PET radioligands, including a one-step radiosynthesis of the clinically used compounds [11C]UCB-J and [11C]PHNO. We further outline the direct utility of this protocol for preclinical PET imaging and its translation to automated radiosynthesis for routine radiotracer production in human clinical imaging. We also demonstrate this protocol for the installation of other diverse and pharmaceutically useful isotopes, including carbon-14, carbon-13 and deuterium.

Underwater acoustic surface waves on a periodically perforated metal plate.

Acoustic surface waves are supported at the surface of appropriately structured elastic materials. Here the excitation and propagation of the lowest-order surface mode supported by a square array of open-ended cavities on a metal plate submerged in water is demonstrated. This mode, which has a half-wavelength character in the cavity, arises due to inter-cavity interaction by evanescent diffraction of the pressure field, and forms a band from zero-frequency to an asymptotic limit frequency. The authors perform an acoustic characterization of the pressure field close to the surface of the perforated plate in the 60-100 kHz frequency range; sound is pulsed from a fixed point-like acoustic source, and the evolution of the acoustic field across the sample surface is measured as a function of time and space with a traversing detector. Using Fourier analysis, the dispersion is imaged between points of high-symmetry (Γ,X,M) and at planes in momentum-space at fixed frequencies. Beaming of acoustic energy on the surface over a narrow frequency band was observed, caused by the anisotropic mode dispersion of the acoustic surface wave on the square lattice. The measured dispersion shows good agreement with the predictions of a numerical model.

Ecological Momentary Assessment of Dietary Lapses Across Behavioral Weight Loss Treatment: Characteristics, Predictors, and Relationships with Weight Change.

BACKGROUND: Adherence to dietary prescriptions is critical for successful weight loss and weight loss maintenance. However, research on specific instances of inadherence (lapses) is limited, and findings regarding the frequency, nature, and causes of lapses are mixed. Additionally, no studies have examined lapses over the course of a weight loss program. PURPOSE: In the context of a reduced calorie diet prescribed as part of a behavioral treatment, we aimed to characterize lapse occurrence, examine lapse frequency across treatment, examine predictors of lapses, and assess the relationship between lapses and weight loss. METHODS: Adults (n = 189) enrolled in a 12-month behavioral weight loss program completed ecological momentary assessment (EMA) at baseline, mid-treatment, and end of treatment. At each EMA survey, participants indicated whether a lapse had occurred, and responded to questions assessing situational, environmental, and affective states. RESULTS: Lapse frequency showed a curvilinear relationship over time, such that frequency first decreased and then increased. Lapse frequency at baseline was negatively associated with early and overall weight loss. Lapses most often occurred at home, in the evenings, on the weekends, and entailed eating a forbidden food. Greater overall levels of assessed affective and environmental triggers predicted lapses, and greater momentary hunger and deprivation, and the presence of palatable food, also prospectively predicted lapses. CONCLUSIONS: In addition to characterizing lapse frequency, the current study identified prospective predictors of lapses across treatment. These findings support the importance of lapses to weight control and provide insight for potential targets of intervention to prevent lapse occurrence.

Importance of Pain Acceptance in Relation to Headache Disability and Pain Interference in Women With Migraine and Overweight/Obesity.

BACKGROUND: Pain acceptance involves willingness to experience pain and engaging in valued activities while pain is present. Though pain acceptance could limit both headache-related disability and pain interference in individuals with migraine, few studies have addressed this issue. This study evaluated whether higher levels of total pain acceptance and its two subcomponents, pain willingness and activity engagement, were associated with lower levels of headache-related impairment in women who had both migraine and overweight/obesity. METHODS: In this cross-sectional study, participants seeking weight loss and headache relief in the Women's Health and Migraine trial completed baseline measures of pain acceptance (Chronic Pain Acceptance Questionnaire [CPAQ]), headache-related disability (Headache Impact Test-6), and pain interference (Brief Pain Inventory). Migraine headache frequency and pain intensity were assessed daily via smartphone diary. Using CPAQ total and subcomponent (pain willingness and activity engagement) scores, headache frequency, pain intensity, and body mass index (BMI) as predictors in linear regression, headache-related disability, and pain interference were modeled as outcomes. RESULTS: On average, participants (n = 126; age = 38.5 ± 8.2 years; BMI = 35.3 ± 6.6 kg/m2 ) reported 8.4 ± 4.7 migraine days/month and pain intensity of 6.0 ± 1.5 on a 0-10 scale on headache days. After correcting for multiple comparisons (adjusted α = .008), pain willingness was independently associated with both lower headache-related disability (P < .001; ß = -0.233) and pain interference (P < .001; ß = -0.261). Activity engagement was not associated with headache-related disability (P = .128; ß = -0.138) and pain interference (P = .042; ß = -0.154). CPAQ total score was not associated with headache-related disability (P = .439; ß = 0.066) and pain interference (P = .305; ß = 0.074). Pain intensity was significantly associated with outcomes in all analyses (Ps < .001; ßs 0.343-0.615). CONCLUSIONS: Higher pain willingness, independent of degree of both migraine severity and overweight, is associated with lower headache-related disability and general pain interference in treatment-seeking women with migraine and overweight/obesity. Future studies are needed to clarify direction of causality and test whether strategies designed to help women increase pain willingness, or relinquish ineffective efforts to control pain, can improve functional outcomes in women who have migraine and overweight/obesity.

Sexual Dysfunction in Women With Migraine and Overweight/Obesity: Relative Frequency and Association With Migraine Severity.

BACKGROUND/OBJECTIVE: Previous studies suggest that migraine might be associated with female sexual dysfunction (FSD), although this association may be complicated by overweight/obesity. To disentangle relationships of migraine and obesity with FSD, we examined: (1) FSD rates in women who had migraine and obesity with a matched sample of women with obesity who were free of migraine and (2) associations between indices of migraine severity and FSD in a larger sample of participants with migraine and overweight/obesity, controlling for important confounders. METHODS: Women with migraine and obesity seeking behavioral weight loss treatment to decrease headaches (n = 37) and nonmigraine controls (n = 37) with obesity seeking weight loss via bariatric surgery were matched on age (±5 years), body mass index (BMI; ±3 kg/m2 ), and reported sexual activity during the past month. Both groups completed the Female Sexual Function Index (FSFI), with a validated FSFI-total cutoff score used to define FSD. In participants with migraine and overweight/obesity (n = 105), separate logistic regression models evaluated associations of migraine attack frequency, intensity, and duration with odds of having FSD, controlling for age, BMI, depression, and anxiety. RESULTS: On average, participants and matched controls had severe obesity (BMI = 42.4 ± 3.8 kg/m2 ; range = 35-49.9) and were 37.3 ± 7.2 years of age (range = 22-50). FSD rate did not differ between migraine participants and controls (56.8% vs. 54.1%, P = .82). In the larger sample of participants with migraine and overweight/obesity (38.2 ± 7.8 years of age; BMI = 34.8 ± 6.4 [range = 25-50 kg/m2 ]; 8.0 ± 4.3 migraine days/month, maximum pain intensity = 5.9 ± 1.4 on 0-10 scale; average attack duration = 18.3 ± 9.7 hours), FSD was not associated with attack frequency (P = .31), pain intensity (P = .92), or attack duration (P = .35) but was associated with more severe anxiety symptoms (Ps < .017). CONCLUSIONS: Rates of sexual dysfunction did not differ in severely obese women with and without migraine. Moreover, indices of migraine severity were not associated with increased risk of FSD in women with overweight/obesity. Replication of present findings in wider populations of women with migraine and of both normal-weight and overweight/obese status are warranted.

Nucleophilic (Radio)Fluorination of α-Diazocarbonyl Compounds Enabled by Copper-Catalyzed H-F Insertion.

The copper-catalyzed H-F insertion into α-diazocarbonyl compounds is described using potassium fluoride (KF) and hexafluoroisopropanol. Access to complex α-fluorocarbonyl derivatives is achieved under mild conditions, and the method is readily adapted to radiofluorination with [(18)F]KF. This late-stage strategy provides an attractive route to (18)F-labeled biomolecules.

Successful weight loss maintenance associated with morning chronotype and better sleep quality.

It is not known whether individuals successful at long term weight loss maintenance differ in chronotype (i.e., being a "morning" or "evening" person) or sleep habits compared to those who are overweight and obese. We compared Morningness-Eveningness Questionnaire (MEQ) and Pittsburgh Sleep Quality Index scores of 690 National Weight Control Registry (NWCR) members (73 % female, 93 % white, age = 51.7 ± 12.5, BMI = 26.4 ± 5.1) to 75 enrollees in two behavioral weight loss interventions (INT; 77 % female, 88 % white, age = 55.7 ± 10.4, BMI = 36.2 ± 4.7). Controlling for age, MEQ scores were higher in NWCR than INT, p = .004, such that more NWCR than INT were morning-types and fewer were evening types, p = .014. Further, NWCR participants reported better sleep quality, longer sleep duration, and shorter latency to sleep onset compared to INT, ps < .05, and fewer NWCR participants reported <6 or <7 h of sleep, ps < .01. Future studies should examine if these factors change as a result of weight loss or are predictors of weight outcome.

Enantioselective radiosynthesis of positron emission tomography (PET) tracers containing [¹8F]fluorohydrins.

Herein, we describe an operationally straightforward radiosynthesis of a chiral transition metal fluoride catalyst, [(18)F](salen)CoF, and its use for late-stage enantioselective aliphatic radiofluorination. We demonstrate the utility of the method by preparing single enantiomer experimental and clinically validated PET tracers that contain base-sensitive functional groups, epimerizable stereocenters, and nitrogen-rich motifs. Unlike the conventional radiosyntheses of these targets with [(18)F]KF, labeling with (salen)CoF is possible in the last step and under exceptionally mild conditions. These results constitute a rare example of a nucleophilic radiofluorination using a transition metal fluoride and highlight the potential of such reagents to enhance traditional methods for labeling aliphatic hydrocarbons.

The Role of the Hand Surgery Consultant in the Care of the Basketball Athlete.

Basketball presents several characteristics that distinguishes it from other contact sports and can influence the manner by which a Team Physician and Hand Surgery Consultant interact. An abbreviated list of pathologies that affect the basketball athlete and the approach to their evaluation and treatment by a Hand Surgeon are described in context of return-to-play.

The Role of the Hand Surgery Consultant in the Care of the Amateur and Professional Golfer.

Golf is unique in this compendium of sports-related hand and wrist injury management. It is the only sport where the ball is stationary and there is no opponent against whom the player is defending. This distinctive sport dates to the 15th century in Scotland and is one of the oldest sports, but it is one where technology has changed many of the fundamental elements-from the "playing field (through advanced in agronomy) and the equipment (club and ball technology).

The Role of the Hand Surgery Consultant in the Management of the High School and Collegiate Athlete.

For the purpose of this article, we will not use individual sports as the primary delineator; however, the two different levels of play: High School and Collegiate. We plan to share insight that we have gained through decades of practice treating High School sports and collegiate athletes. This article offers readers reliable guidance on not only treating the athlete's hand but understanding the person as a whole and the struggles at each level of play.

In Silico Discovery and Subsequent Characterization of Potent 4R-Tauopathy Positron Emission Tomography Radiotracers.

A chemical fingerprint search identified Z3777013540 (1-(5-(6-fluoro-1H-indol-2-yl)pyrimidin-2-yl)piperidin-4-ol; 1) as a potential 4R-tau binding ligand. Binding assays in post-mortem Alzheimer's disease (AD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD) brain with [3H]1 provided KD (nM) values in AD = 4.0, PSP = 5.1, and CBD = 4.5. In vivo positron emission tomography (PET) imaging in rats with [18F]1 demonstrated good brain penetration and rapid clearance from normal brain tissues. A subsequent molecular similarity search using 1 as the query revealed an additional promising compound, Z4169252340 (4-(5-(6-fluoro-1H-indol-2-yl)pyrimidin-2-yl)morpholine; 21). Binding assays with [3H]21 provided KD (nM) values in AD = 1.2, PSP = 1.6, and CBD = 1.7 and lower affinities for binding aggregated α-synuclein and amyloid-beta. PET imaging in rats with [18F]21 demonstrated a higher brain penetration than [18F]1 and rapid clearance from normal brain tissues. We anticipate that 1 and 21 will be useful for the identification of other potent novel 4R-tau radiotracers.

A Novel Brain PET Radiotracer for Imaging Alpha Synuclein Fibrils in Multiple System Atrophy.

Abnormal α-synuclein (α-syn) aggregation characterizes α-synucleinopathies, including Parkinson's disease (PD) and multiple system atrophy (MSA). However, no suitable positron emission tomography (PET) radiotracer for imaging α-syn in PD and MSA exists currently. Our structure-activity relationship studies identified 4-methoxy-N-(4-(3-(pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)phenyl)benzamide (4i) as a PET radiotracer candidate for imaging α-syn. In vitro assays revealed high binding of 4i to recombinant α-syn fibrils (inhibition constant (Ki) = 6.1 nM) and low affinity for amyloid beta (Aß) fibrils in Alzheimer's disease (AD) homogenates. However, [3H]4i also exhibited high specific binding to AD, progressive supranuclear palsy, and corticobasal degeneration tissues as well as PD and MSA tissues, suggesting notable affinity to tau. Nevertheless, the specific binding to pathologic α-syn aggregates in MSA post-mortem brain tissues was significantly higher than in PD tissues. This finding demonstrated the potential use of [11C]4i as a PET tracer for imaging α-syn in MSA patients. Nonhuman primate PET studies confirmed good brain uptake and rapid washout for [11C]4i.

Lessons Learned in the Care of the Professional Athlete.

The role of an experienced Hand Surgery Consultant within the complete care matrix for a professional sports organization has evolved in my 3-decade career. Granted, hand injuries may have been demoted in this population where ACL tears, shoulder dislocations, and Lisfranc injuries seem to have much greater visibility, but our experience has told us that Hand injuries often contribute to the most surgeries per team/per season and can result in significant man-game loss of service. In my 30 years as a Consultant, Team Physician and/or Medical Director in all 4 major North American-based Leagues (as well as for "itinerant" independent contractor sports of golf, tennis, and motorsports), we have cared for well over 2000 athletes. This privilege has provided us with unparalleled exposure to the locker rooms, training rooms, and clubhouses for almost every team in professional-level competition and many elite-level collegiate programs. My goal in assembling this volume was to highlight the skilled and experienced colleagues who have contributed so much to the surgical science of caring for the hand and wrist in the professional athlete and furthering the logic of having a Hand Surgeon on "speed dial" for our fellow Team Physicians who want to provide optimal care for their athletes. Regrettably, until recently, the limited number of us who had significant involvement in this cohort probably fell short of engaging in scientific inquiry and publishing our observations or series. I will accept more than my share of that shortcoming, but as these practices have expanded in number and the exposure went from anecdotal to voluminous, our community started to communicate within Hand Surgery ranks, but now we want to share our knowledge with all professional involved in elite athlete care. This collection is not meant to be an exhaustive review of individual pathologies. Fortunately, valued colleagues have done a laudable job of chronicling the common-to-complex pathologies that we see in sports coverage This publication is styled less from the "what" and "how" standpoint, aimed instead at providing Team Physicians with the "when" and "why" of optimizing their player's outcomes through collaboration with their Hand Specialist.

The Role of the Hand Surgery Consultant in the Care of the Baseball Athlete.

The approach to the care of baseball athletes and organizations is influenced by 2 factors that distinguish it from other sports: the number of contests and the number of players. America's pastime is a marathon that can (if successful in the regular season and postseason play) stretch over a 10-months, 162+-game schedule. In addition, unlike other major North American sports, baseball's "feeder system" is the highly-structured Minor League Baseball. This is in contradistinction to caring for 15 basketball players who arrive at the professional level through collegiate (or even high school) play or 20 hockey players that may have had an NCAA experience or come through the Junior Leagues in Canada. Even though a 53-man football roster can keep a Hand Surgery Consultant busy, it is still a limited professional level cohort that is one-third to one-fourth of the size of baseball's and is played across less than 20 contests. Granted, every sport has its own culture-which is why we have developed this format for this publication-but planning for the scope of baseball care is also influenced by the unique pace and intensity of the interactions, that is why it is called a "clubhouse," rather than a "locker room". With these fundamentals shared, let us expand on what our experience has taught us about the care for athletes that are engaged in batting, throwing, receiving, and colliding on the diamond.

Screening of σ2 Receptor Ligands and In Vivo Evaluation of 11C-Labeled 6,7-Dimethoxy-2-[4-(4-methoxyphenyl)butan-2-yl]-1,2,3,4-tetrahydroisoquinoline for Potential Use as a σ2 Receptor Brain PET Tracer.

In this study, a panel of 46 compounds containing five different scaffolds known to have high σ2 receptor affinity were screened. 6,7-Dimethoxy-2-[4-(4-methoxyphenyl)butan-2-yl]-1,2,3,4-tetrahydroisoquinoline [(±)-7] (Ki for σ1 = 48.4 ± 7.7 nM, and Ki for σ2 = 0.59 ± 0.02 nM) and its desmethyl analogue, (±)-8 (Ki for σ1 = 108 ± 35 nM, and Ki for σ2 = 4.92 ± 0.59 nM), showed excellent binding affinity and subtype selectivity for σ2 receptors. In vitro cell binding indicated that σ2 receptor binding of [11C]-(±)-7 and [11C]-(±)-8 was dependent on TMEM97 protein expression. In PET studies, the peak brain uptake of [11C]-(±)-7 (8.28 ± 2.52%ID/cc) was higher than that of [11C]-(±)-8 (4.25 ± 0.97%ID/cc) with specific distribution in the cortex and hypothalamus. Brain uptake or tissue binding was selectively inhibited by ligands with different σ2 receptor binding affinities. The results suggest [11C]-(±)-7 can be used as a PET radiotracer for imaging the function of σ2 receptors in central nervous system disorders.

Regioselective semihydrogenation of dienes.

A one-pot, three-step strategy for the regioselective semihydrogenation of dienes is described. This procedure uses 9-BBN-H as a temporary protective group for alkenes. Yields range from 55% to 95%, and the reaction is tolerant of a variety of common functional groups. Additionally, the final elimination step of the sequence can be replaced with a peroxide-mediated alkylborane oxidation, generating regioselectively semihydrogenated product alcohols.

PARP Targeted Alpha-Particle Therapy Enhances Response to PD-1 Immune-Checkpoint Blockade in a Syngeneic Mouse Model of Glioblastoma.

We have previously demonstrated potent antitumor effects of PARP targeted alpha-therapy with astatine-211-MM4 ([211At]MM4) in neuroblastoma preclinical models, although differential sensitivity suggests it is unlikely to be curative as a single-agent in all tumor types. Alpha-particle induced DNA damage can elicit an immune response that results in T-cell activation against tumor cells; however, tumor cells can evade immune surveillance through expression of programmed death ligand 1 (PD-L1). Therefore, we investigated the effects of α particle therapy in combination with immune-checkpoint blockade using astatine-211-MM4 and anti-programmed death receptor 1 (anti-PD-1) immunotherapy in a syngeneic mouse model of glioblastoma. We characterized the sensitivity of four human glioblastoma cell lines to [211At]MM4 in vitro. To evaluate [211At]MM4 treatment effects on hematological tissues, complete blood counts were performed after a single dose at 12, 24, or 36 MBq/kg. In vivo efficacy was evaluated in a syngeneic mouse model of glioblastoma using GL26 glioblastoma cells in CB57BL/6J mice treated with either 36 MBq/kg [211At]MM4, anti-PD-1 antibody, or a combination of the two. Following a single dose of [211At]MM4, lymphocytes are significantly decreased compared to control at both 72 h and 1 week following treatment followed by recovery of counts by 2 weeks. However, neutrophils showed an increase with all dose levels of [211At]MM4 exhibiting higher levels than control. The average best tumor responses for combination, anti-PD-1, and [211At]MM4 were 100%, 83.6%, and 58.2% decrease in tumor volume, respectively. Average progression free intervals for combination, anti-PD-1, [211At]MM4, and control groups was 65, 36.4, 23.2, and 3 days, respectively. The percentages of disease-free mice at the end of the study for combination and anti-PD-1 were 100% and 60%, while [211At]MM4 and control groups were both 0%. In summary, combination therapy was more effective than either single agent in all response categories analyzed, highlighting the potential for PARP targeted alpha-therapy to enhance PD-1 immune-checkpoint blockade.

An efficient synthesis of (+/-)-grandisol featuring 1,5-enyne metathesis.

An eight-step synthesis of (+/-)-grandisol features a key sequence involving a high-yielding, microwave-assisted enyne metathesis to yield a 1-alkenylcyclobutene that is semihydrogenated to yield a silyl-protected grandisol. Metathesis catalyst screens revealed an intriguing trend whereby substrate conversion correlated strongly with the identity of the ligands on the catalyst. In addition, new reactivity of 1-alkenylcyclobutenes toward hydrogenation is described.

A radiocarpal ligament reconstruction using brachioradialis for secondary ulnar translation of the carpus following radiocarpal dislocation: a cadaver study.

PURPOSE: Radiocarpal dislocation damages the radiocarpal ligaments, typically eliminating the possibility for repair. The goals of this study were to create a model for ulnar translation of the carpus and design a soft-tissue reconstruction using the brachioradialis (BR) to prevent ulnar translation of the carpus. We primarily sought to recreate the stabilizing effect of the radioscaphocapitate ligament. METHODS: Eight cadaveric upper limbs were dissected, leaving only the BR tendon. The wrist was loaded perpendicular to the long axis of the forearm, and load-displacement curves for ulnar translation were generated. The radiocarpal ligaments were sectioned. Substantial ulnar translation was seen only after complete release of the palmar and dorsal radiocarpal ligaments. Reconstruction was performed with the BR tendon, maintaining the insertion on the radial styloid. The proximal tendon stump was brought distally through a drill hole in the center of the capitate, palmar to dorsal, and secured to the dorsal rim of the radius with a suture anchor. The specimens were then retested after this reconstruction. Qualitative evaluation of graphs plotted, mini c-arm fluoroscopy, and visual observation was also performed. RESULTS: Comparison of the intact specimens and the specimens after sectioning of the radiocarpal ligaments revealed a significant difference between mean ulnar translation (11.1 mm vs 18.4 mm; p < 0.05). Comparison of the sectioned specimens before and after BR reconstruction demonstrated a statistically significant difference in mean ulnar translation (18.4 mm vs 10.6 mm; p < 0.05). Comparison of the intact specimens and the specimens after sectioning-reconstruction did not demonstrate a significant difference, indicating that the BR reconstruction re-established the stability seen in the intact specimens with regard to ulnar translation (11.1 mm vs 10.6 mm; p > 0.05). CONCLUSIONS: The model consistently produced significant ulnar translation after division of the radiocarpal ligaments. The BR reconstruction was primarily designed to restore the function of the radioscaphocapitate ligament. This biomechanical study demonstrates the ability of this reconstruction to generate a statistically significant restraint to ulnar translation in a cadaver model of radiocarpal dislocation.