Changes in Physiology before, during, and after Yawning

The ultimate function of yawning continues to be debated. Here, we examine physiological measurements taken before, during, and after yawns in humans, in an attempt to identify key proximate mechanisms associated with this behavior. In two separate studies we measured changes in heart rate, lung volume, eye closure, skin conductance, ear pulse, respiratory sinus arrhythmia, and respiratory rate. Data were depicted from 75 s before and after yawns, and analyzed at baseline, during, and immediately following yawns. Increases in heart rate, lung volume, and eye muscle tension were observed during or immediately following yawning. Patterns of physiological changes during yawning were then compared to data from non-yawning deep inhalations. In one study, respiration period increased following the execution of a yawn. Much of the variance in physiology surrounding yawning was specific to the yawning event. This was not the case for deep inhalation. We consider our findings in light of various hypotheses about the function of yawning and conclude that they are most consistent with the brain cooling hypothesis

PET Imaging of Fatty Acid Amide Hydrolase with [18F]DOPP in Nonhuman Primates

Fatty acid amide hydrolase (FAAH) regulates endocannabinoid signaling. [11C]CURB, an irreversibly binding FAAH inhibitor, has been developed for clinical research imaging with PET. However, no fluorine-18 labeled radiotracer for FAAH has yet advanced to human studies. [18F]DOPP ([18F]3-(4,5-dihydrooxazol-2-yl)phenyl (5-fluoropentyl)carbamate) has been identified as a promising 18F-labeled analogue based on rodent studies. The goal of this work is to evaluate [18F]DOPP in nonhuman primates to support its clinical translation. High specific activity [18F]DOPP (5–6 Ci·μmol–1) was administered intravenously (iv) to three baboons (2M/1F, 3–4 years old). The distribution and pharmacokinetics were quantified following a 2 h dynamic imaging session using a simultaneous PET/MR scanner. Pretreatment with the FAAH-selective inhibitor, URB597, was carried out at 200 or 300 μg/kg iv, 10 min prior to [18F]DOPP administration. Rapid arterial blood sampling for the first 3 min was followed by interval sampling with metabolite analysis to provide a parent radiotracer plasma input function that indicated ∼95% baseline metabolism at 60 min and a reduced rate of metabolism after pretreatment with URB597. Regional distribution data were analyzed with 1-, 2-, and 3-tissue compartment models (TCMs), with and without irreversible trapping since [18F]DOPP covalently links to the active site of FAAH. Consistent with previous findings for [11C]CURB, the 2TCM with irreversible binding was found to provide the best fit for modeling the data in all regions. The composite parameter λk3 was therefore used to evaluate whole brain (WB) and regional binding of [18F]DOPP. Pretreatment studies showed inhibition of λk3 across all brain regions (WB baseline: 0.112 mL/cm3/min; 300 μg/kg URB597: 0.058 mL/cm3/min), suggesting that [18F]DOPP binding is specific for FAAH, consistent with previous rodent data

Mannose-Binding Lectin Binds to Amyloid Protein and Modulates Inflammation

Mannose-binding lectin (MBL), a soluble factor of the innate immune system, is a pattern recognition molecule with a number of known ligands, including viruses, bacteria, and molecules from abnormal self tissues. In addition to its role in immunity, MBL also functions in the maintenance of tissue homeostasis. We present evidence here that MBL binds to amyloid β peptides. MBL binding to other known carbohydrate ligands is calcium-dependent and has been attributed to the carbohydrate-recognition domain, a common feature of other C-type lectins. In contrast, we find that the features of MBL binding to Aβ are more similar to the reported binding characteristics of the cysteine-rich domain of the unrelated mannose receptor and therefore may involve the MBL cysteine-rich domain. Differences in MBL ligand binding may contribute to modulation of inflammatory response and may correlate with the function of MBL in processes such as coagulation and tissue homeostasis

First Human Use of a Radiopharmaceutical Prepared by Continuous-Flow Microfluidic Radiofluorination: Proof of Concept with the Tau Imaging Agent [F]T807

Despite extensive preclinical imaging with radiotracers developed by continuous-flow microfluidics, a positron emission tomographic (PET) radiopharmaceutical has not been reported for human imaging studies by this technology. The goal of this study was to validate the synthesis of the tau radiopharmaceutical 7-(6-fluoropyridin-3-yl)-5H-pyrido[4,3-b]indole ([ 18 F]T807) and perform first-in-human PET scanning enabled by microfluidic flow chemistry. [ 18 F]T807 was synthesized by our modified one-step method and adapted to suit a commercial microfluidic flow chemistry module. For this proof of concept, the flow system was integrated to a GE Tracerlab FX FN unit for high-performance liquid chromatography purification and formulation. Three consecutive productions of [ 18 F]T807 were conducted to validate this radiopharmaceutical. Uncorrected radiochemical yields of 17 ± 1% of crude [ 18 F]T807 (≈ 500 mCi, radiochemical purity 95%) were obtained from the microfluidic device. The crude material was then purified, and > 100 mCi of the final product was obtained in an overall uncorrected radiochemical yield of 5 ± 1% ( n = 3), relative to starting [ 18 F]fluoride (end of bombardment), with high radiochemical purity (≥ 99%) and high specific activities (6 Ci/μmol) in 100 minutes. A clinical research study was carried out with [ 18 F]T807, representing the first reported human imaging study with a radiopharmaceutical prepared by this technology

PET Imaging of Fatty Acid Amide Hydrolase with [¹⁸F]DOPP in Nonhuman Primates

Fatty acid amide hydrolase (FAAH) regulates endocannabinoid signaling. [¹¹C]­CURB, an irreversibly binding FAAH inhibitor, has been developed for clinical research imaging with PET. However, no fluorine-18 labeled radiotracer for FAAH has yet advanced to human studies. [¹⁸F]­DOPP ([¹⁸F]­3-(4,5-dihydrooxazol-2-yl)­phenyl (5-fluoropentyl)­carbamate) has been identified as a promising ¹⁸F-labeled analogue based on rodent studies. The goal of this work is to evaluate [¹⁸F]­DOPP in nonhuman primates to support its clinical translation. High specific activity [¹⁸F]­DOPP (5–6 Ci·μmol^–1) was administered intravenously (iv) to three baboons (2M/1F, 3–4 years old). The distribution and pharmacokinetics were quantified following a 2 h dynamic imaging session using a simultaneous PET/MR scanner. Pretreatment with the FAAH-selective inhibitor, URB597, was carried out at 200 or 300 μg/kg iv, 10 min prior to [¹⁸F]­DOPP administration. Rapid arterial blood sampling for the first 3 min was followed by interval sampling with metabolite analysis to provide a parent radiotracer plasma input function that indicated ∼95% baseline metabolism at 60 min and a reduced rate of metabolism after pretreatment with URB597. Regional distribution data were analyzed with 1-, 2-, and 3-tissue compartment models (TCMs), with and without irreversible trapping since [¹⁸F]­DOPP covalently links to the active site of FAAH. Consistent with previous findings for [¹¹C]­CURB, the 2TCM with irreversible binding was found to provide the best fit for modeling the data in all regions. The composite parameter <i>λk</i>₃ was therefore used to evaluate whole brain (WB) and regional binding of [¹⁸F]­DOPP. Pretreatment studies showed inhibition of <i>λk</i>₃ across all brain regions (WB baseline: 0.112 mL/cm³/min; 300 μg/kg URB597: 0.058 mL/cm³/min), suggesting that [¹⁸F]­DOPP binding is specific for FAAH, consistent with previous rodent data

Quantitative in vivo mapping of myocardial mitochondrial membrane potential

Background: Mitochondrial membrane potential (ΔΨm) arises from normal function of the electron transport chain. Maintenance of ΔΨm within a narrow range is essential for mitochondrial function. Methods for in vivo measurement of ΔΨm do not exist. We use 18F-labeled tetraphenylphosphonium (18F-TPP+) to measure and map the total membrane potential, ΔΨT, as the sum of ΔΨm and cellular (ΔΨc) electrical potentials. Methods: Eight pigs, five controls and three with a scar-like injury, were studied. Pigs were studied with a dynamic PET scanning protocol to measure 18F-TPP+ volume of distribution, VT. Fractional extracellular space (fECS) was measured in 3 pigs. We derived equations expressing ΔΨT as a function of VT and the volume-fractions of mitochondria and fECS. Seventeen segment polar maps and parametric images of ΔΨT were calculated in millivolts (mV). Results: In controls, mean segmental ΔΨT = -129.4±1.4 mV (SEM). In pigs with segmental tissue injury, ΔΨT was clearly separated from control segments but variable, in the range -100 to 0 mV. The quality of ΔΨT maps was excellent, with low noise and good resolution. Measurements of ΔΨT in the left ventricle of pigs agree with previous in in-vitro measurements. Conclusions: We have analyzed the factors affecting the uptake of voltage sensing tracers and developed a minimally invasive method for mapping ΔΨT in left ventricular myocardium of pigs. ΔΨT is computed in absolute units, allowing for visual and statistical comparison of individual values with normative data. These studies demonstrate the first in vivo application of quantitative mapping of total tissue membrane potential, ΔΨT

First Human Use of a Radiopharmaceutical Prepared by Continuous-Flow Microfluidic Radiofluorination: Proof of Concept with the Tau Imaging Agent [ 18

Despite extensive preclinical imaging with radiotracers developed by continuous-flow microfluidics, a positron emission tomographic (PET) radiopharmaceutical has not been reported for human imaging studies by this technology. The goal of this study was to validate the synthesis of the tau radiopharmaceutical 7-(6-fluoropyridin-3-yl)-5H-pyrido[4,3-b]indole ([ 18 F]T807) and perform first-in-human PET scanning enabled by microfluidic flow chemistry. [ 18 F]T807 was synthesized by our modified one-step method and adapted to suit a commercial microfluidic flow chemistry module. For this proof of concept, the flow system was integrated to a GE Tracerlab FX FN unit for high-performance liquid chromatography purification and formulation. Three consecutive productions of [ 18 F]T807 were conducted to validate this radiopharmaceutical. Uncorrected radiochemical yields of 17 ± 1% of crude [ 18 F]T807 (≈ 500 mCi, radiochemical purity 95%) were obtained from the microfluidic device. The crude material was then purified, and > 100 mCi of the final product was obtained in an overall uncorrected radiochemical yield of 5 ± 1% ( n = 3), relative to starting [ 18 F]fluoride (end of bombardment), with high radiochemical purity (≥ 99%) and high specific activities (6 Ci/μmol) in 100 minutes. A clinical research study was carried out with [ 18 F]T807, representing the first reported human imaging study with a radiopharmaceutical prepared by this technology