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9 pages, 6 figures, 1 table, supplement https://doi.org/10.5194/essd-15-511-2023-supplement.-- Data availability: Data are archived in the data repository PANGAEA (https://doi.org/10.1594/PANGAEA.929968) (Strydom et al., 2022).-- Code availability: R scripts used to generate figures and maps can be found in the Supplement, Seagrass meadows provide valuable socio-ecological ecosystem services, including a key role in climate change mitigation and adaption. Understanding the natural history of seagrass meadows across environmental gradients is crucial to deciphering the role of seagrasses in the global ocean. In this data collation, spatial and temporal patterns in seagrass meadow structure, biomass and production data are presented as a function of biotic and abiotic habitat characteristics. The biological traits compiled include measures of meadow structure (e.g. percent cover and shoot density), biomass (e.g. above-ground biomass) and production (e.g. shoot production). Categorical factors include bioregion, geotype (coastal or estuarine), genera and year of sampling. This dataset contains data extracted from peer-reviewed publications published between 1975 and 2020 based on a Web of Science search and includes 11 data variables across 12 seagrass genera. The dataset excludes data from mesocosm and field experiments, contains 14 271 data points extracted from 390 publications and is publicly available on the PANGAEA® data repository (https://doi.org/10.1594/PANGAEA.929968; Strydom et al., 2021). The top five most studied genera are Zostera, Thalassia, Cymodocea, Halodule and Halophila (84 % of data), and the least studied genera are Phyllospadix, Amphibolis and Thalassodendron (2.3 % of data). The data hotspot bioregion is the Tropical Indo-Pacific (25 % of data) followed by the Tropical Atlantic (21 %), whereas data for the other four bioregions are evenly spread (ranging between 13 and 15 % of total data within each bioregion). From the data compiled, 57 % related to seagrass biomass and 33 % to seagrass structure, while the least number of data were related to seagrass production (11 % of data). This data collation can inform several research fields beyond seagrass ecology, such as the development of nature-based solutions for climate change mitigation, which include readership interested in blue carbon, engineering, fisheries, global change, conservation and policy, Anna Lafratta was supported by Environmental Protection Authority (SA)/Water SA and Edith Cowan University (ECU) Industry Engagement Scholarship. Cristian Salinas was funded by ECU Higher Degree by Research Scholarship. Oscar Serrano was supported by I+D+i projects RYC2019-027073-I and PIE HOLOCENO 20213AT014 funded by MCIN/AEI/10.13039/501100011033 and FEDER, With the institutional support of the ‘Severo Ochoa Centre of Excellence’ accreditation (CEX2019-000928-S)

Objective To investigate Tau pathology using multimodal biomarkers of neurodegeneration and neurocognition in participants with myotonic dystrophy type 1 (DM1). Methods We recruited twelve participants with DM1 and, for comparison, two participants with Alzheimer’s Disease (AD). Participants underwent cognitive screening and social cognition testing using the Dépistage Cognitif de Québec (DCQ), among other tests. Biomarkers included Tau PET with [18F]-AV-1451, CSF (Aβ, Tau, phospho-Tau), and plasma (Aβ, Tau, Nf-L, GFAP) studies. Results Of the twelve DM1 participants, seven completed the full protocol (Neurocognition 11/12; PET 7/12, CSF 9/12, plasma 12/12). Three DM1 participants were cognitively impaired (CI). On average, CI DM1 participants had lower scores on the DCQ compared to cognitively unimpaired (CU) DM1 participants (75.5/100 vs. 91.4/100) and were older (54 vs. 44 years old) but did not differ in years of education (11.3 vs. 11.1). The majority (6/7) of DM1 participants had no appreciable PET signal. Only one of the CI participants presented with elevated Tau PET SUVR in bilateral medial temporal lobes. This participant was the eldest and most cognitively impaired, and had the lowest CSF Aβ 1-42 and the highest CSF Tau levels, all suggestive of co-existing AD. CSF Tau and phospho-Tau levels were higher in the 3 CI compared to CU DM1 participants, but with a mean value lower than that typically observed in AD. Nf-L and GFAP were elevated in most DM1 participants (9/11 and 8/11, respectively). Finally, CSF phospho-Tau was significantly correlated with plasma Nf-L concentrations. Conclusions and relevance We observed heterogenous cognitive and biomarker profiles in individuals with DM1. While some participants presented with abnormal PET and/or CSF Tau, these patterns were highly variable and only present in a small subset. Although DM1 may indeed represent a non-AD Tauopathy, the Tau-PET tracer used in this study was unable to detect an in vivo Tau DM1 signature in this small cohort. Interestingly, most DM1 participants presented with elevated plasma Nf-L and GFAP levels, suggestive of other, possibly related, central brain alterations which motivate further research. This pioneering study provides novel insights towards the potential relationship between biomarkers and neurocognitive deficits commonly seen in DM1.

Seagrass meadows provide valuable socio-ecological ecosystem services, including a key role in climate change mitigation and adaption. Understanding the natural history of seagrass meadows across environmental gradients is crucial to decipher the role of seagrasses in the global ocean. In this data collation, spatial and temporal patterns in seagrass meadow structure, biomass, production and reproduction data are presented as a function of biotic and abiotic habitat characteristics. The biological traits compiled include measures of meadow structure (e.g., percent cover and shoot density), biomass (e.g., above-ground biomass), production (e.g., shoot production), and reproduction effort (e.g., flowering intensity and seed bank density). Categorical factors include bioregion, geotype (coastal or estuarine), genera and year of sampling. This dataset contains data extracted from peer-reviewed publications published between 1975 and 2020 based on a Web of Science search, and includes 15 data variables across 12 seagrass genera. The top four most studied genera are Zostera, Thalassia, Halophila and Cymodocea (80 % of data), and the least studied genera are Phyllospadix, Amphibolis and Thalassodendron (2.3 % of data). The data hotspot bioregion is the Tropical Indo Pacific (25 % of data), whereas data for the other five bioregions are evenly spread (ranging between 13 and 16 % of total data within each bioregion). From the data compiled, 39 % related to seagrass biomass, while the least number of data were related to seagrass production (10 % of data). This data collation can inform several research fields beyond seagrass ecology, such as the development of nature-based solutions for climate change mitigation, which include readership interested in blue carbon, engineering, fisheries, global change, conservation and policy.

Este artículo contiene 12 páginas, 4 figuras, 3 tablas., Seagrass ecosystems rank amongst the most efficient natural carbon sinks on earth, sequestering CO2 through photosynthesis and storing organic carbon ( Corg) underneath their soils for millennia and thereby, mitigating climate change. However, estimates of Corg stocks and accumulation rates in seagrass meadows (blue carbon) are restricted to few regions, and further information on spatial variability is required to derive robust global estimates. Here we studied soil Corg stocks and accumulation rates in seagrass meadows across the Colombian Caribbean. We estimated that Thalassia testudinum meadows store 241 ± 118 Mg Corg ha− 1 (mean ± SD) in the top 1 m-thick soils, accumulated at rates of 122 ± 62 and 15 ± 7 g Corg m− 2 year− 1 over the last ~ 70 years and up to 2000 years, respectively. The tropical climate of the Caribbean Sea and associated sediment runoff, together with the relatively high primary production of T. testudinum, influencing biotic and abiotic drivers of Corg storage linked to seagrass and soil respiration rates, explains their relatively high Corg stocks and accumulation rates when compared to other meadows globally. Differences in soil Corg storage among Colombian Caribbean regions are largely linked to differences in the relative contribution of Corg sources to the soil Corg pool (seagrass, algae Halimeda tuna, mangrove and seston) and the content of soil particles < 0.016 mm binding Corg and enhancing its preservation. Despite the moderate areal extent of T. testudinum in the Colombian Caribbean (661 km2), it sequesters around 0.3 Tg CO2 year− 1, which is equivalent to ~ 0.4% of CO2 emissions from fossil fuels in Colombia. This study adds data from a new region to a growing dataset on seagrass blue carbon and further explores differences in meadow Corg storage based on biotic and abiotic environmental factors, while providing the basis for the implementation of seagrass blue carbon strategies in Colombia., external actions ENV/2016/380-526 cofounded by INVEMAR and Fundación Natura (Colombia,) with the support of ECU (Australia) and CSIC (project COOPB20366, I-COOP+ program, Spain). Its contents are the sole responsibility of the authors and do not necessarily reflect the views of the European Union. O.S. was supported by an ARC DECRA (DE170101524). C.S. was supported by ECU Higher Degree by Research Scholarship. P.M. was supported by the Australian Research Council LIEF Project (LE170100219). The IAEA is grateful for the support provided to its Environment Laboratories by the Government of the Principality of Monaco. This is the Contribution #1306 from INVEMAR.

Seagrass meadows store globally significant organic carbon (Corg) stocks which, if disturbed, can lead to CO2 emissions, contributing to climate change. Eutrophication and thermal stress continue to be a major cause of seagrass decline worldwide, but the associated CO2 emissions remain poorly understood. This study presents comprehensive estimates of seagrass soil Corg erosion following eutrophication‐driven seagrass loss in Cockburn Sound (23 km2 between 1960s and 1990s) and identifies the main drivers. We estimate that shallow seagrass meadows (5 m), however, soil Corg stocks in seagrass and bare but previously vegetated areas were not significantly different (2.6 ± 0.3 and 3.0 ± 0.6 kg Corg/m2, respectively). The soil Corg sequestration capacity prevailed in shallow and deep vegetated areas (55 ± 11 and 21 ± 7 g Corg m−2 year−1, respectively), but was lost in bare areas. We identified that seagrass canopy loss alone does not necessarily drive changes in soil Corg but, when combined with high hydrodynamic energy, significant erosion occurred. Our estimates point at ~0.20 m/s as the critical shear velocity threshold causing soil Corg erosion. We estimate, from field studies and satellite imagery, that soil Corg erosion (within the top 50 cm) following seagrass loss likely resulted in cumulative emissions of 0.06–0.14 Tg CO2‐eq over the last 40 years in Cockburn Sound. We estimated that indirect impacts (i.e. eutrophication, thermal stress and light stress) causing the loss of ~161,150 ha of seagrasses in Australia, likely resulted in the release of 11–21 Tg CO2 ‐eq since the 1950s, increasing cumulative CO2 emissions from land‐use change in Australia by 1.1%–2.3% per annum. The patterns described serve as a baseline to estimate potential CO2 emissions following disturbance of seagrass meadows., Seagrasses constitute carbon sink hotspots, but when disturbed the soil carbon stocks become exposed to erosion fuelling CO2 emissions and climate change. We identified that seagrass canopy loss alone does not necessarily result in soil carbon loss but, when combined with high hydrodynamic energy at the sediment surface (>0.20 m/s), significant erosion occurred. Indirect impacts causing the loss of ~161,150 ha of seagrasses in Australia, such as eutrophication, thermal stress and light stress, likely resulted in the release of 11–21 Tg CO2‐eq since the 1950s, increasing cumulative CO2 emissions from land‐use change in Australia by 1.1%–2.3% per annum.

Tidal marshes rank among the ecosystems with the highest capacity to sequester and store organic carbon (Corg) on earth. To inform conservation of coastal vegetated ecosystems for climate change mitigation, this study investigated the factors driving variability in carbon storage. We estimated soil Corg stocks in tidal marshes across temperate Western Australia and assessed differences among geomorphic settings (marine and fluvial deltas, and mid-estuary) and vegetation type (Sarcocornia quinqueflora and Juncus kraussii) linked to soil biogeochemistry. Soil Corg stocks within fluvial and mid-estuary settings were significantly higher (209 ± 14 and 211 ± 20 Mg Corg ha−1, respectively; 1-m-thick soils) than in marine counterparts (156 ± 12 Mg Corg ha−1), which can be partially explained by higher preservation of soil Corg in fluvial and mid-estuary settings rich in fine-grained (org stocks were not significantly different between S. quinqueflora and J. kraussii marshes (185 ± 13 and 202 ± 13 Mg Corg ha−1, respectively). The higher contribution of tidal marsh plus supratidal vegetation in fluvial (80%) and intermediate (76%) compared to marine (57%) settings further explains differences in soil Corg stocks. The estimated soil Corg stocks in temperate Western Australia’s tidal marshes (57 Tg Corg within ~ 3000 km2 extent) correspond to about 2% of worldwide tidal marsh soil Corg stocks. The results obtained identify global drivers of soil Corg storage in tidal marshes and can be used to target hot spots for climate change mitigation based on tidal marsh conservation.

The measurement of receptor occupancy (RO) using positron emission tomography (PET) has been instrumental in guiding discovery and development of CNS directed therapeutics. We and others have investigated muscarinic acetylcholine receptor 4 (M4) positive allosteric modulators (PAMs) for the treatment of symptoms associated with neuropsychiatric disorders. In this article, we describe the synthesis, in vitro, and in vivo characterization of a series of central pyridine-related M4 PAMs that can be conveniently radiolabeled with carbon-11 as PET tracers for the in vivo imaging of an allosteric binding site of the M4 receptor. We first demonstrated its feasibility by mapping the receptor distribution in mouse brain and confirming that a lead molecule 1 binds selectively to the receptor only in the presence of the orthosteric agonist carbachol. Through a competitive binding affinity assay and a number of physiochemical properties filters, several related compounds were identified as candidates for in vivo evaluation. These candidates were then radiolabeled with 11C and studied in vivo in rhesus monkeys. This research eventually led to the discovery of the clinical radiotracer candidate [11C]MK-6884.

Este artículo contiene 15 páginas, 6 figuras, 1 tabla., Seagrass meadows rank among the most significant organic carbon (Corg) sinks on earth. We examined the variability in seagrass soil Corg stocks and composition across Australia and identified the main drivers of variability, applying a spatially hierarchical approach that incorporates bioregions and geomorphic settings. Top 30 cm soil Corg stocks were similar across bioregions and geomorphic settings (min-max: 20–26 Mg Corg ha−1), but meadows formed by large species (i.e., Amphibolis spp. and Posidonia spp.) showed higher stocks (24–29 Mg Corg ha−1) than those formed by smaller species (e.g., Halodule, Halophila, Ruppia, Zostera, Cymodocea, and Syringodium; 12–21 Mg Corg ha−1). In temperate coastal meadows dominated by large species, soil Corg stocks mainly derived from seagrass Corg (72 ± 2%), while allochthonous Corg dominated soil Corg stocks in meadows formed by small species in temperate and tropical estuarine meadows (64 ± 5%). In temperate coastal meadows, soil Corg stocks were enhanced by low hydrodynamic exposure associated with high mud and seagrass Corg contents. In temperate estuarine meadows, soil Corg stocks were enhanced by high contributions of seagrass Corg, low to moderate solar radiation, and low human pressure. In tropical estuarine meadows formed by small species, large soil Corg stocks were mainly associated with low hydrodynamic energy, low rainfall, and high solar radiation. These results showcase that bioregion and geomorphic setting are not necessarily good predictors of soil Corg stocks and that site-specific estimates based on local environmental factors are needed for Blue Carbon projects and greenhouse gases accounting purposes., This study was delivered as part of the Pilot Projects program of the Land Restoration Fund, supported by the Queensland Government, Deakin University, The University of Queensland, James Cook University, CSIRO, HSBC, Qantas, Australian Government Department of Industry, Science, Energy and Resources, NQ Dry Tropics, Great Barrier Reef Foundation and Greencollar. We are thankful for the funding provided by Deakin University (to PIM and MDPC), Qantas (to PIM and MDPC) and HSBC (to PIM and MDPC). MR, PY, PIM were supported through ARC Linkage grant LP160100492, and PIM and CEL were supported through ARC Linkage grant LP160100242. NJW is funded through Australian Government National Environment Science Program (Tropical Water Quality Hub). MFA was funded through an Advance Queensland Industry Research Fellowship, Queensland Government. CS was funded by ECU Higher Degree by Research Scholarship

Alzheimer's disease (AD) is an irreversible, progressive brain disorder that impairs memory and cognitive function. Dysregulation of the amyloid-β (Aβ) pathway and amyloid plaque accumulation in the brain are hallmarks of AD. Aducanumab is a human, immunoglobulin gamma 1 monoclonal antibody targeting aggregated forms of Aβ. In phase Ib and phase III studies, aducanumab reduced Aβ plaques in a dose dependent manner, as measured by standard uptake value ratio of amyloid positron emission tomography imaging. The goal of this work was to develop a quantitative systems pharmacology model describing the production, aggregation, clearance, and transport of Aβ as well as the mechanism of action for the drug to understand the relationship between aducanumab dosing regimens and changes of different Aβ species, particularly plaques in the brain. The model was used to better understand the pharmacodynamic effects observed in the clinical trials of aducanumab and assist in the clinical development of future Aβ therapies.

To investigate Tau pathology using multimodal biomarkers of neurodegeneration and neurocognition in participants with myotonic dystrophy type 1 (DM1).We recruited twelve participants with DM1 and, for comparison, two participants with Alzheimer's Disease (AD). Participants underwent cognitive screening and social cognition testing using the Dépistage Cognitif de Québec (DCQ), among other tests. Biomarkers included Tau PET with [18F]-AV-1451, CSF (Aβ, Tau, phospho-Tau), and plasma (Aβ, Tau, Nf-L, GFAP) studies.Of the twelve DM1 participants, seven completed the full protocol (Neurocognition 11/12; PET 7/12, CSF 9/12, plasma 12/12). Three DM1 participants were cognitively impaired (CI). On average, CI DM1 participants had lower scores on the DCQ compared to cognitively unimpaired (CU) DM1 participants (75.5/100 vs. 91.4/100) and were older (54 vs. 44 years old) but did not differ in years of education (11.3 vs. 11.1). The majority (6/7) of DM1 participants had no appreciable PET signal. Only one of the CI participants presented with elevated Tau PET SUVR in bilateral medial temporal lobes. This participant was the eldest and most cognitively impaired, and had the lowest CSF Aβ 1-42 and the highest CSF Tau levels, all suggestive of co-existing AD. CSF Tau and phospho-Tau levels were higher in the 3 CI compared to CU DM1 participants, but with a mean value lower than that typically observed in AD. Nf-L and GFAP were elevated in most DM1 participants (9/11 and 8/11, respectively). Finally, CSF phospho-Tau was significantly correlated with plasma Nf-L concentrations.We observed heterogenous cognitive and biomarker profiles in individuals with DM1. While some participants presented with abnormal PET and/or CSF Tau, these patterns were highly variable and only present in a small subset. Although DM1 may indeed represent a non-AD Tauopathy, the Tau-PET tracer used in this study was unable to detect an in vivo Tau DM1 signature in this small cohort. Interestingly, most DM1 participants presented with elevated plasma Nf-L and GFAP levels, suggestive of other, possibly related, central brain alterations which motivate further research. This pioneering study provides novel insights towards the potential relationship between biomarkers and neurocognitive deficits commonly seen in DM1.

Excess nitrogen (N) is one of the most widespread and serious pollutants in the environment, but wetlands can reduce N loads, ameliorating its damaging effects downstream. Tropical wetlands are highly productive and experience high temperatures year-round, resulting in potentially high denitrification rates. However, few measurements of denitrification have been reported for tropical wetlands. In this study, we measured denitrification within stands of macrophytes at the edge of a tropical lake (900 m length, 4 m deep) in Australia. We compared denitrification rates among sediments under emergent grass (giant bulrush, Actinoscirpus grossus), sediments under floating waterlilies (Nymphae spp.), and sediments from the deeper sections of the lagoon with no macrophytes. We also measured the denitrification and primary productivity of the epiphyton on macrophytes and compared the rates with those from the sediment. Denitrification in the sediment was higher (Dt = 3.3���52 mg m���2 h���1) than denitrification of the epiphyton (Dt = 1.9���3.6 mg m���2 h���1) and was mostly coupled with nitrification (Dn). Denitrification was highest in sediments rich in organic carbon (32.3%) and N (1.4%), and during times of the year when nitrates (NOx���-N = NO2���-N + NO3���-N) concentrations were relatively high (>0.10 mg L���1). Denitrification was lowest in sediments with no macrophytes, which comprised most of the lake area. Denitrification rates of sediments under these macrophyte stands were among the highest values measured for natural wetlands and highlight the potential role of this process in ameliorating N pollution in tropical catchments.

Background: Spiders are among the most venomous animals in nature. Their venom constitutes a source of novel and innovative peptides and proteins with medicinal and biotechnological interest. However, their potential as antimicrobial, anti-cancerous, anti-hypertensive and even in the modulation of nociception is under-studied, mainly because handling the venom is technically challenging and there is paucity of next-generation-sequencing (NGS) data. Due to the increasing evidence of underestimation of the number of genes by the use of a single transcriptome assembler, we re-assembled and optimized the de novo transcriptome of the venom gland of the recently described Colombian spider P. verdolaga, by using three free access algorithms: Trinity, Soapdenovo and SPAdes. All the assemblies were evaluated by statistical parameters (e.g. contigs, GC%, max and min length and N50), by applying BUSCO´s terms retrieval against the arthropod data set to determine the best assembly for each software.Results: Our analyses show that while approximately 54% of all the assembled and structurally annotated sequences could be found in all three algorithms, around 23% of these were unique for Trinity and 21% were unique for SPAdes. The non-redundant merge of all three assemblies’ output permitted the annotation of 8640 sequences; at least 15% more when compared to each software separately, and an increase of 20% when compared to a previous P. verdolaga assembly. Analysis of the annotated genes allowed the identification of unreported lectins, kinins and over 200 peptides and proteins with potential antimicrobial and protease inhibition activities. Furthermore, homology search against the Arachnoserver database and the EROP knowledgebase allowed the identification of 135 novel theraphotoxins of biotechnological interest.Conclusion: Transcriptomic data is of utmost importance for spiders, as it is one of the more feasible and scalable ways to characterize these organisms. However, the use of a single de novo assembler implies an under representation of the expressed sequences, as it has been shown here. In the generation of data for non-model organisms as well as in the search for novel peptides and proteins with biotechnological interest, it is highly recommended that at least two different assemblers are employed.

The measurement of receptor occupancy (RO) using positron emission tomography (PET) has been instrumental in guiding discovery and development of CNS directed therapeutics. We and others have investigated muscarinic acetylcholine receptor 4 (M4) positive allosteric modulators (PAMs) for the treatment of symptoms associated with neuropsychiatric disorders. In this article, we describe the synthesis, in vitro, and in vivo characterization of a series of central pyridine-related M4 PAMs that can be conveniently radiolabeled with carbon-11 as PET tracers for the in vivo imaging of an allosteric binding site of the M4 receptor. We first demonstrated its feasibility by mapping the receptor distribution in mouse brain and confirming that a lead molecule

Seagrass ecosystems, which have important functions such as coastal protection and blue carbon sequestration, are threatened by anthropogenic pressure including climate change. Long-term data series from seagrass sedimentary archives (mats) can be used to understand natural cycles of environmental change and answer key questions related to contemporary management. A 7500 yr sediment record from Posidonia australis meadows in Oyster Harbour (Albany, SW Australia) was subjected to multiproxy reconstruction by means of pigment analysis (UHPLC), analytical pyrolysis (Py-GC–MS), carbonate content, δ13C and δ15N stable isotope ratios, organic C (Corg) content, Corg/N ratio and glomalin-related soil proteins (GRSP). The study revealed a brackish lagoon (7500–7000 cal yr BP) that was transformed in an open marine environment (7000–4100 cal yr BP) due to Holocene transgression. Earliest evidence of seagrass establishment was detected around 4500 cal yr BP, and meadow extension accelerated between 4100 and 3700 cal yr BP. The meadow environment was surprisingly resistant against environmental perturbations, as the mat, composed of P. australis seagrass fibres embedded within a siliciclastic mineral matrix containing biogenic carbonates, continued to develop steadily until 190 cal yr BP (1830 CE). Then, shifts in several proxies (pigments, GRSP) showed evidence of terrestrial runoff-triggered eutrophication/turbidity (likely driven by forest clearance and agricultural activities after European settlement), but the seagrass showed resilience (no decline of the proportion of seagrass-derived Corg). By contrast, since ~1930 CE seagrass retreat is evident in the biogeochemical record: lighter δ13C values, lower lignin abundance and shifts in pigment abundance and types, affecting the balance between seagrass inputs and alternative sources, as was observed in previous studies of the area. The findings show that pigment proxies are useful early indicators of shifts in seagrass ecosystem condition, while lignocellulose and other pyrolysis products are useful proxies of more profound ecosystem alterations that influence seagrass abundance. The record indicates that the climax seagrass ecosystem condition, which prevailed for several millennia, had been impacted over the last century. Management of seagrass and coastal ecosystems should aim to avoid crossing ecological thresholds and diminish local impacts aggravating those of global change.

18F-MK-6240 (18F-labeled 6-(fluoro)-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine) is a highly selective, subnanomolar-affinity PET tracer for imaging neurofibrillary tangles (NFTs). Plasma kinetics, brain uptake, and preliminary quantitative analysis of 18F-MK-6240 in healthy elderly (HE) subjects, subjects with clinically probable Alzheimer disease (AD), and subjects with amnestic mild cognitive impairment were characterized in a study that is, to our knowledge, the first to be performed on humans. Methods: Dynamic PET scans of up to 150 min were performed on 4 cognitively normal HE subjects, 4 AD subjects, and 2 amnestic mild cognitive impairment subjects after a bolus injection of 152–169 MBq of 18F-MK-6240 to evaluate tracer kinetics and distribution in brain. Regional SUV ratio (SUVR) and distribution volume ratio were determined using the cerebellar cortex as a reference region. Total distribution volume was assessed by compartmental modeling using radiometabolite-corrected input function in a subgroup of 6 subjects. Results:18F-MK-6240 had rapid brain uptake with a peak SUV of 3–5, followed by a uniformly quick washout from all brain regions in HE subjects; slower clearance was observed in regions commonly associated with NFT deposition in AD subjects. In AD subjects, SUVR between 60 and 90 min after injection was high (approximately 2–4) in regions associated with NFT deposition, whereas in HE subjects, SUVR was approximately 1 across all brain regions, suggesting high tracer selectivity for binding NFTs in vivo. 18F-MK-6240 total distribution volume was approximately 2- to 3-fold higher in neocortical and medial temporal brain regions of AD subjects than in HE subjects and stabilized by 60 min in both groups. Distribution volume ratio estimated by the Logan reference tissue model or compartmental modeling correlated well (R2 > 0.9) to SUVR from 60 to 90 min for AD subjects. Conclusion:18F-MK-6240 exhibited favorable kinetics and high binding levels to brain regions with a plausible pattern for NFT deposition in AD subjects. In comparison, negligible tracer binding was observed in HE subjects. This pilot study suggests that simplified ratio methods such as SUVR can be used to quantify NFT binding. These results support further clinical development of 18F-MK-6240 for potential application in longitudinal studies.

[18F]MK-6240 is a selective, high-affinity PET radiotracer for imaging neurofibrillary tangles (NFT) in Alzheimer’s disease (AD). Herein, we report test–retest (T–RT) reproducibility of [18F]MK-6240 in AD and healthy volunteers (HV). Twelve subjects with AD and three cognitively normal HV were enrolled in the study and dynamically scanned for 150 min with [18F]MK-6240 under a T–RT protocol. Two radioactivity doses were investigated: 165 ± 3 MBq (n = 6) and 300 ± 40 MBq (n = 9). Serial arterial blood samples were taken for each scan to obtain metabolite-corrected input functions. Following intravenous administration of [18F]MK-6240, the tracer rapidly partitioned into the brain and its heterogenous distribution pattern was consistent with known NFT pathology in AD. In contrast, uptake in HV was low and uniform across the brain parenchyma. Across all subjects, average T–RT variabilities in NFT-rich regions were ∼21%, ∼14% and ∼6% for various quantitative metrics: total distribution volume (VT), binding potential (BPND), and standardized uptake ratio (SUVR90–120), respectively. No significant differences in SUVR T–RT variability were observed between the high and low injected radioactivity groups (5.6% and 6.1%, respectively). This work suggests [18F]MK-6240 has adequate SUVR T–RT characteristics supporting the use of this outcome in future studies.

Este artículo contiene 10 páginas, 3 tablas, 2 figuras., Policies aiming to preserve vegetated coastal ecosystems (VCE; tidal marshes, mangroves and seagrasses) to mitigate greenhouse gas emissions require national assessments of blue carbon resources. Here, we present organic carbon (C) storage in VCE across Australian climate regions and estimate potential annual CO2 emission benefits of VCE conservation and restoration. Australia contributes 5–11% of the C stored in VCE globally (70–185 Tg C in aboveground biomass, and 1,055–1,540 Tg C in the upper 1m of soils). Potential CO2 emissions from current VCE losses are estimated at 2.1–3.1 Tg CO2-e yr-1, increasing annual CO2 emissions from land use change in Australia by 12–21%. This assessment, the most comprehensive for any nation to-date, demonstrates the potential of conservation and restoration of VCE to underpin national policy development for reducing greenhouse gas emissions., This project was supported by the CSIRO Marine and Coastal Carbon Biogeochemical Cluster, CSIRO Oceans and Atmosphere, the ECU Faculty Research Grant Scheme and Early Career Research Grant Schemes, UTS Plant Functional Biology and Climate Change Cluster, NSW Southeast Local Land Services, Department of Environment, Land, Water and Planning (DELWP), Parks Victoria, Victorian Coastal Catchment Management Authorities (GHCMA, CCMA, PPWCMA, WGCMA, EGCMA), University of Queensland Centennial Scholarship, Hodgkin Trust Scholarship, Australian Institute of Nuclear Science and Engineering, Northern Territory Government Innovation Grant, Australian Research Council (DE130101084, DE140101733, DE150100581, DE160100443, DE170101524, DP150103286, DP150102092, DP160100248, DP160100248, DP180101285, LE140100083, LE170100219, LP150100519, LP160100242 and LP110200975), the Generalitat de Catalunya (MERS 2014 SGR-1356), the ICTA ‘Unit of Excellence’ (MinECo, MDM2015-0552), Obra Social “LaCaixa”, SUMILEN, CTM 2013-47728-R, Ministry of Economy and Competitiveness and UKM-DIP-2017- 005.

A PET tracer is desired to help guide the discovery and development of disease-modifying therapeutics for neurodegenerative diseases characterized by neurofibrillary tangles (NFTs), the predominant tau pathology in Alzheimer disease (AD). We describe the preclinical characterization of the NFT PET tracer 18F-MK-6240. Methods: In vitro binding studies were conducted with 3H-MK-6240 in tissue slices and homogenates from cognitively normal and AD human brain donors to evaluate tracer affinity and selectivity for NFTs. Immunohistochemistry for phosphorylated tau was performed on human brain slices for comparison with 3H-MK-6240 binding patterns on adjacent brain slices. PET studies were performed with 18F-MK-6240 in monkeys to evaluate tracer kinetics and distribution in the brain. 18F-MK-6240 monkey PET studies were conducted after dosing with unlabeled MK-6240 to evaluate tracer binding selectivity in vivo. Results: The 3H-MK-6240 binding pattern was consistent with the distribution of phosphorylated tau in human AD brain slices. 3H-MK-6240 bound with high affinity to human AD brain cortex homogenates containing abundant NFTs but bound poorly to amyloid plaque–rich, NFT-poor AD brain homogenates. 3H-MK-6240 showed no displaceable binding in the subcortical regions of human AD brain slices and in the hippocampus/entorhinal cortex of non-AD human brain homogenates. In monkey PET studies, 18F-MK-6240 displayed rapid and homogeneous distribution in the brain. The 18F-MK-6240 volume of distribution stabilized rapidly, indicating favorable tracer kinetics. No displaceable binding was observed in self-block studies in rhesus monkeys, which do not natively express NFTs. Moderate defluorination was observed as skull uptake. Conclusion:18F-MK-6240 is a promising PET tracer for the in vivo quantification of NFTs in AD patients.

Neurofibrillary tangles (NFTs) made up of aggregated tau protein have been identified as the pathologic hallmark of several neurodegenerative diseases including Alzheimer's disease. In vivo detection of NFTs using PET imaging represents a unique opportunity to develop a pharmacodynamic tool to accelerate the discovery of new disease modifying therapeutics targeting tau pathology. Herein, we present the discovery of 6-(fluoro-(18)F)-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine, 6 ([(18)F]-MK-6240), as a novel PET tracer for detecting NFTs. 6 exhibits high specificity and selectivity for binding to NFTs, with suitable physicochemical properties and in vivo pharmacokinetics.

Amyloid beta (Aβ) deposition and cognitive decline are key features of Alzheimer's disease. The relationship between Aβ status and changes in neuronal function over time, however, remains unclear. We evaluated the effect of baseline Aβ status on reference region spontaneous brain activity (SBA-rr) using resting-state functional magnetic resonance imaging and fluorodeoxyglucose positron emission tomography in patients with mild cognitive impairment. Patients (N = 62, [43 Aβ-positive]) from the Alzheimer's Disease Neuroimaging Initiative were divided into Aβ-positive and Aβ-negative groups via prespecified cerebrospinal fluid Aβ42 or 18F-florbetapir positron emission tomography standardized uptake value ratio cutoffs measured at baseline. We analyzed interaction of biomarker-confirmed Aβ status with SBA-rr change over a 2-year period using mixed-effects modeling. SBA-rr differences between Aβ-positive and Aβ-negative subjects increased significantly over time within subsystems of the default and visual networks. Changes exhibit an interaction with memory performance over time but were independent of glucose metabolism. Results reinforce the value of resting-state functional magnetic resonance imaging in evaluating Alzheimer'’s disease progression and suggest spontaneous neuronal activity changes are concomitant with cognitive decline.

Our identification of dysregulation of the AKT pathway in ovarian cancer as a platinum resistance specific event led to a comprehensive analysis of in vitro, in vivo and clinical behaviour of the AKT inhibitor GSK2141795. Proteomic biomarker signatures correlating with effects of GSK2141795 were developed using in vitro and in vivo models, well characterised for related molecular, phenotypic and imaging endpoints. Signatures were validated in temporally paired biopsies from patients treated with GSK2141795 in a clinical study. GSK2141795 caused growth-arrest as single agent in vitro, enhanced cisplatin-induced apoptosis in vitro and reduced tumour volume in combination with platinum in vivo. GSK2141795 treatment in vitro and in vivo resulted in ~50-90% decrease in phospho-PRAS40 and 20-80% decrease in fluoro-deoxyglucose (FDG) uptake. Proteomic analysis of GSK2141795 in vitro and in vivo identified a signature of pathway inhibition including changes in AKT and p38 phosphorylation and total Bim, IGF1R, AR and YB1 levels. In patient biopsies, prior to treatment with GSK2141795 in a phase 1 clinical trial, this signature was predictive of post-treatment changes in the response marker CA125. Development of this signature represents an opportunity to demonstrate the clinical importance of AKT inhibition for re-sensitisation of platinum resistant ovarian cancer to platinum.

Oxytocin is known to be implicated in a variety of functions, such as learning, stress, anxiety, feeding, and pain perception. Oxytocin is also important for social memory and attachment, human bonding, sexual and maternal behaviour, and aggression. Human disorders characterized by aberrant social interactions, such as autism and schizophrenia, may also involve abnormal oxytocin levels. GSK712043, GSK711320, and GSK664004, three antagonists exhibiting subnanomolar affinity for the human oxytocin receptor (hOTR) and high selectivity over vasopressin receptors were successfully labelled with carbon-11 with suitable yields (0.5-1GBq @EOS), high molar activity (275-700 GBq/mu mol), and radiochemical purities. The in vivo regional uptake of these radiotracers was determined in porcine brain. [C-11]GSK711320 baseline scan showed no significant brain uptake, and limited initial uptake was observed following administration of [C-11]GSK712043 or [C-11]GSK664004. The [C-11]GSK712043 and [C-11]GSK664004 kinetics were slow and peaked at around 2%ID/L at 90 minutes post-injection. For both tracers, the distribution of activity was homogeneous throughout the brain. All the tracers showed high uptake in the pituitary gland, especially [C-11]GSK711320; however, its uptake could not be blocked by pretreatment with the known OTR antagonist, L368,899. In vivo evaluation of these candidates demonstrated that they are not suitable as central OTR PET imaging agents.

We characterized the relationship between the plasma concentration of the phospodiesterase (PDE)-4 inhibitor GSK356278 and occupancy of the PDE4 enzyme in the brain of healthy volunteers, using the positron emission tomography (PET) tracer [11C](R)-rolipram. To this end, PET scans were acquired in eight male volunteers before and at 3 and 8 h after a single 14 mg oral dose of GSK356278. A metabolite-corrected arterial input function was used in conjunction with the dynamic PET emission data to estimate volumes of distribution (VT) from a two-tissue compartment model. The administration of GSK356278 reduced [11C](R)-rolipram whole brain VT by 17% at 3 h post-dose (p = 0.01) and by 4% at 8 h post-dose. The mean plasma Cmax was 42.3 ng/ml, leading to a PDE4 occupancy of 48% at Tmax. The in vivo affinity of GSK356278 was estimated as EC50 = 46 ± 3.6 ng/ml. We present the first report of a direct estimation of PDE4 blockade in the living human brain. In vivo affinity of GSK356278 for the PDE4, estimated in this early phase study, was combined with GSK356278 safety and tolerability data to decide on a therapeutic dose for future clinical development.

In aquatic ecosystems, the potential effects of toxic compounds are greatly determined by their physicochemical forms and bioavailability. The aim of this work was the assessment of metal toxicity to the green alga Pseudokirchneriella subcapitata in contaminated water samples of an urban river (Matanza-Riachuelo, Argentina). A total of 30 samples were analyzed. Physicochemical parameters and total and dissolved metal (Cd, Cu, Cr, Pb, Ni and Zn) concentrations were measured. Toxicity was related as a function of size fractionation and chemical speciation (using the program Mineql+) in the dissolved fraction (

Overfishing has affected the population abundance trends of many commercial fish species. In the Amazon, the fishery of a catfish commonly known as "mota" or "piracatinga" (Calophysus macropterus) has become an important economic activity in the region as this species has replaced a number of other overexploited great catfish species in the markets. Due to this high exploitation, ways in which to increase captures have been identified. One strategy is to use decomposing animal carcasses as bait. Such strategy has increased the hunting pressure on endangered species such as caimans and river dolphins. We investigated which catfish species are currently commercialized in Colombian fish markets using DNA barcoding, and measured mercury concentration in the tissues of fish molecularly identified as C. macropterus. We collected 86 fish samples in markets of four Colombian cities. Sixty-eight of these were identified molecularly as C.macropterus. The mercury concentration of 29 such samples was analyzed. Samples presented total Hg concentrations higher than the limit for human consumption established by the WHO (0.5 μg/g). These results are worrisome and suggest that (1) C. macropterus is a widely used fish species for human consumption in Colombia and (2) C. macropterus has high concentrations of total Hg, making its consumption a public health risk. Results presented here suggest that C. macropterus has replaced capaz in most Colombian markets. This fishery threatens wild species of river dolphins and caimans, and is also a public health risk given the high mercury levels we found in a subsample of these fishes.

The selection of a therapeutically meaningful dose of a novel pharmaceutical is a crucial step in drug development. Positron emission tomography (PET) allows the in vivo estimation of the relationship between the plasma concentration of a drug and its target occupancy, optimizing dose selection and reducing the time and cost of early development. Triple reuptake inhibitors (TRIs), also referred to as serotonin-norepinephrine-dopamine reuptake inhibitors, enhance monoaminergic neurotransmission by blocking the action of the monoamine transporters, raising extracellular concentrations of those neurotransmitters. GSK1360707 [(1R,6S)-1-(3,4-dichlorophenyl)-6-(methoxymethyl)-4-azabicyclo[4.1.0]heptane] is a novel TRI that until recently was under development for the treatment of major depressive disorder; its development was put on hold for strategic reasons. We present the results of an in vivo assessment of the relationship between plasma exposure and transporter blockade (occupancy). Studies were performed in baboons (Papio anubis) to determine the relationship between plasma concentration and occupancy of brain serotonin reuptake transporter (SERT), dopamine reuptake transporter (DAT), and norepinephrine uptake transporter (NET) using the radioligands [(11)C]DASB [(N,N-dimethyl-2-(2-amino-4-cyanophenylthio) benzylamine], [(11)C]PE2I [N-(3-iodoprop-2E-enyl)-2β-carbomethoxy-3β-(4-methylphenyl)nortropane], and [(11)C]2-[(2-methoxyphenoxy)phenylmethyl]morpholine (also known as [(11)C]MRB) and in humans using [(11)C]DASB and [(11)C]PE2I. In P. anubis, plasma concentrations resulting in half-maximal occupancy at SERT, DAT, and NET were 15.16, 15.56, and 0.97 ng/ml, respectively. In humans, the corresponding values for SERT and DAT were 6.80 and 18.00 ng/ml. GSK1360707 dose-dependently blocked the signal of SERT-, DAT-, and NET-selective PET ligands, confirming its penetration across the blood-brain barrier and blockade of all three monoamine transporters in vivo.

In vivo characterization of the brain pharmacokinetics of novel compounds provides important information for drug development decisions involving dose selection and the determination of administration regimes. In this context, the compound-target affinity is the key parameter to be estimated. However, if compounds exhibit a dynamic lag between plasma and target bound concentrations leading to pharmacological hysteresis, care needs to be taken to ensure the appropriate modeling approach is used so that the system is characterized correctly and that the resultant estimates of affinity are correct. This work focuses on characterizing different pharmacokinetic models that relate the plasma concentration to positron emission tomography outcomes measurements (e.g., volume of distribution and target occupancy) and their performance in estimating the true in vivo affinity. Measured (histamine H3 receptor antagonist—GSK189254) and simulated data sets enabled the investigation of different modeling approaches. An indirect pharmacokinetic-receptor occupancy model was identified as a suitable model for the calculation of affinity when a compound exhibits pharmacological hysteresis.

[(11)C]-(+)-PHNO is a D3 preferring PET radioligand which has recently opened the possibility of imaging D3 receptors in the human brain in vivo. This imaging tool allows characterisation of the distribution of D3 receptors in vivo and further investigation of their functional role. The specific [(11)C]-(+)-PHNO signal is a mixture of D3 and D2 components with the relative magnitude of each component determined by the regional receptor densities. An accurate and reproducible delineation of regions of interest (ROI) is therefore important for optimal analysis of human PET data. We present a set of anatomical guidelines for the delineation of D3 relevant ROIs including substantia nigra, hypothalamus, ventral pallidum/substantia innominata, ventral striatum, globus pallidus and thalamus. Delineation of these structures using this approach allowed for high intra- and inter-operator reproducibility. Subsequently we used a selective D3 antagonist to dissect the total [(11)C]-(+)-PHNO signal in each region into its D3 and D2 components and estimated the regional fraction of the D3 signal (f(PHNO)(D3)). In descending order of magnitude the following results for the f(PHNO)(D3) were obtained: hypothalamus=100%, substantia nigra=100%, ventral pallidum/substantia innominata=75%, globus pallidus=65%, thalamus=43%, ventral striatum=26% and precommissural-ventral putamen=6%. An automated approach for the delineation of these anatomical regions of interest was also developed and investigated in terms of its reproducibility and accuracy.

The passage of drugs in and out of the brain is controlled by the blood—brain barrier (BBB), typically, using either passive diffusion across a concentration gradient or active transport via a protein carrier. In-vitro and preclinical measurements of BBB penetration do not always accurately predict the in-vivo situation in humans. Thus, the ability to assay the concentration of novel drug candidates in the human brain in vivo provides valuable information for derisking of candidate molecules early in drug development. Here, positron emission tomography (PET) measurements are combined with in-vitro equilibrium dialysis assays to enable assessment of transport and estimation of the free brain concentration in vivo. The PET and equilibrium dialysis data were obtained for 36 compounds in the pig. Predicted P-glycoprotein (P-gp) status of the compounds was consistent with the PET/equilibrium dialysis results. In particular, Loperamide, a well-known P-gp substrate, exhibited a significant concentration gradient consistent with active efflux and after inhibition of the P-gp process the gradient was removed. The ability to measure the free brain concentration and assess transport of novel compounds in the human brain with combined PET and equilibrium dialysis assays can be a useful tool in central nervous system (CNS) drug development.

We measured the whole-body distribution of IV-injected [11C]GSK215083, a new 5-HT6 antagonist PET tracer, as a function of time in adult subjects, in order to determine the radiation exposure. After injection with a single bolus of [11C]GSK215083 (range 330–367 MBq; mean 346 MBq), PET emission data were acquired for approximately 120 min in six subjects (three males and three females). Five organs were identified as exhibiting uptake above background. For these, regions of interest were delineated on emission images, and time–activity curves (TAC) generated. Residence times were calculated as the area under the curve of the TAC, normalized to injected activities and standard values of organ volumes. Dosimetry calculations were then performed using the computer program OLINDA/EXM 1.0. The mean effective dose averaged over both males and females (±standard deviation) was estimated to be 7.7 ± 1.0 μSv/MBq (male 7.0 ± 0.4; female 8.5 ± 0.6). For the effective dose equivalent, the corresponding values are 7.8 ± 1.2 μSv/MBq (male 6.8 ± 0.5; female 8.9 ± 0.1). The organ receiving the highest dose was the lung, with an average equivalent dose of 25.6 ± 6.9 μSv/MBq (male 20.8 ± 5.6; female 30.4 ± 4.4). The estimated radiation dose for [11C]GSK215083 is consistent with those for other neuroreceptor ligands labeled with carbon-11. The somewhat higher dose estimate for females compared to males may reflect the difference in observed residence times and representative differences in the male and female phantoms used for dosimetry calculations. Based on conventionally accepted dose limits, [11C]GSK215083 may be used for multiple PET scans in the same subject.

The current interest in developing Glycine transporter Type 1 (GlyT- 1) inhibitors, for diseases such as schizophrenia, has led to the demand for a GlyT-1 PET molecular imaging tool to aid drug development and dose selection. We report on ( 11 C)GSK931145 as a novel GlyT-1 imaging probe in primate and man. Primate PET studies were performed to determine the level of specific binding following homologous competition with GSK931145 and the plasma-occupancy relationship of the GlyT-1 in- hibitor GSK1018921. Human PET studies were performed to determine the test-retest reproducibility of ( 11 C)GSK931145 and the plasma-occupancy relationship of GSK1018921. ( 11 C)GSK931145 entered primate and human brain and yielded a heter- ogeneous pattern of uptake which was similar in both species with highest uptake in midbrain, thalamus, and cerebellum. Homologous competition in primates indicated no viable reference region and gave binding potential estimates between 1.5 and 3 for midbrain, thalamus and cerebellum, While the distribution and binding potential val- ues were similar across species, both the plasma free fraction (fP: 0.8 vs. 8%) and delivery (K1: 0.025 vs. 0.126 ml cm 23 min 21 ) were significantly lower in humans. Test-retest reproducibility in humans calculated using a two tissue compartmental model was poor (VAR(VT): 29-38%), but was improved using a pseudo reference tissue model (VAR(BPND): 16-23%). GSK1018921 EC50 estimates were 22.5 and 45.7 ng/ml in primates and humans, respectively. Synapse 65:1319-1332, 2011. V C 2011 Wiley-Liss, Inc.

The type-1 glycine transporter (GlyT1) is an important target for the development of new medications for schizophrenia. A specific and selective positron emission tomography (PET) GlyT1 ligand would facilitate drug development studies to determine whether a drug reaches this target and help establish suitable doses for clinical trials. This article describes the evaluation of three candidate GlyT1 PET radioligands (GSK931145, GSK565710, and GSK991022) selected from a library of compounds based on favorable physicochemical and pharmacological properties. Each candidate was successfully labeled using [11C]methyl iodide or [11C]methyl triflate and administered to a pig pre- and postadministration with a pharmacological dose of a GlyT1 inhibitor to determine their suitability as PET ligands in the porcine brain in vivo. All three candidate ligands were analyzed quantitatively with compartment analyses employing a plasma input function. [11C]GSK931145 showed good brain penetration and a heterogeneous distribution in agreement with reported GlyT1 localization. Following pretreatment with GSK565710, uptake of [11C]GSK931145 was reduced to homogeneous levels. Although [11C]GSK565710 also showed good brain penetration and a heterogeneous distribution, the apparent level of specific binding was reduced compared to [11C]GSK931145. In contrast, [11C]GSK991022 showed a much lower brain penetration and resultant signal following pretreatment with GSK565710. Based on these findings [11C]GSK931145 was identified as the most promising ligand for imaging GlyT1 in the porcine brain, possessing good brain penetration, specific signal, and reversible kinetics. [11C]GSK931145 is now being progressed into higher species. Synapse 64:542–549, 2010. © 2010 Wiley-Liss, Inc.

An appropriate mathematical model is required for quantitative analysis of high affinity radioligands as direct or surrogate probes to measure receptor distribution, affinity, concentration, binding potential, and endogenous or exogenous ligand occupancy levels. For studies with positron emission tomography (PET) or single photon emission computed tomography (SPECT), the receptor-ligand compartment model has been well established and widely used. This pharmacokinetic model is represented mathematically by a set of nonlinear ordinary differential equations. Variations of models for PET and SPECT account for radioactive decay differently. These are not equivalent and entail assumptions or approximations that may be not appreciated. In this study, a general form of the model is presented and compared with others with various approximations, which are valid only under specific conditions. The various approximate formulations were analytically compared to the exact model to identify the terms that were neglected in the approximate formulations. The extent to which the approximations impact the model solutions was assessed by computer simulations based on numerical solutions to each set of equations. Specifically, each model formulation was tested using three simulated injection protocols representing a typical PET experiment, a typical SPECT experiment, and an extreme experiment where both the injected activity and themore » specific activity were very high. No significant differences were found among the output of the three model formulations when the PET and SPECT injection protocols were tested. The only conditions that produced significant differences occurred when the specific activity and the administered activity were simultaneously very high. These conditions, however, have little practical relevance to experimentally achievable conditions due to radiation dose and specific activity of radiopharmaceuticals.« less

AKT (a serine/threonine-specific protein kinase) regulates many cellular processes contributing to cytotoxic drug resistance. This study’s primary objective examined the relationship between GSK2141795, an oral, pan-AKT inhibitor, and 18F-FDG PET markers of glucose metabolism in tumor tissue to determine whether 18F-FDG PET could be used to guide personalized dosing of GSK2141795. Biomarker analysis of biopsies was also undertaken. Methods: Twelve patients were enrolled in 3 cohorts; all underwent dynamic 18F-FDG PET scans and serial pharmacokinetic sampling at baseline, week 2, and week 4 with tumor biopsies before treatment and at week 4. Response was evaluated by RECIST v1.1 and Gynecologic Cancer Intergroup criteria. Biopsy samples were analyzed for mutations and protein expression. Results: GSK2141795 did not significantly influence blood glucose levels. No dose–response relationship was observed between GSK2141795 pharmacokinetics and 18F-FDG PET pharmacodynamic measures; however, an exposure–response relationship was seen between maximum drug concentrations and maximal decrease in 18F-FDG uptake in the best-responding tumor. This relationship also held for pharmacokinetic parameters of exposure and 1,5-anhydroglucitol (a systemic measure of glucose metabolism). Phospho-AKT upregulation at week 4 in biopsies confirmed AKT inhibition by GSK2141795. Single-agent activity was observed with a clinical benefit rate of 27% (3/11) and 30% (3/10) CA125 response in the study’s platinum-resistant ovarian patients. AKT pathway activation by PIK3CA/PIK3R1 mutation did not correlate with clinical activity, whereas RAS/RAF pathway mutations did segregate with resistance to AKT inhibition. Conclusion: GSK2141795 demonstrated an exposure–response relationship with decreased 18F-FDG uptake and is active and tolerable. This study’s design integrating 18F-FDG PET, pharmacokinetics, and biomarker analyses demonstrates the potential for clinical development for personalized treatment.