(e)Managing the uncertainty of tuberculosis in the post-Soviet limbo: Tracking prisoners' coerced mobility for treatment in Ukrainian prisons.

The collapse of the Soviet Union triggered an escalation of the tuberculosis (TB) epidemic in many post-Soviet countries, including Ukraine. The main reasons for this situation include both the approach to TB care and the concentration of TB cases in prisons. The neoliberal approach to TB care system reform promises the optimization of treatment terms, "dehospitalization" and "despecialization" of the system of care, and a different type of control, established through digital technologies. One such technology is the "e-TB Manager", which was designated as a national TB registry, including in the prison system in 2012. In prison, where everyone "is to be fixed" and isolated, the uncertainty of patients' movements seems to be avoided by pre-existing conditions. In practice, however, the vertically aligned, centralized organizational structure of the post-Soviet prison implies a constant need to link its elements together through "coerced" mobility carried out in secrecy. Treatment in exile may not be the primary goal of such a practice, but it becomes the result when prisoners from numerous prison facilities are sent to a limited number of prison TB hospitals. The integration of the e-TB Manager as a tool to enable the tracking of patient movements and, consequently, improve the efficiency of diagnostic and treatment processes in prison, can be seen as both a purely technical measure and a "magic bullet". In this article, we argue that, in the case of Ukrainian prisons, the neoliberal approach and the Soviet socialist approach to gaining control over TB indeed adapt and reinforce each other but fail to compete meaningfully. The fragmented implementation of one is absorbed by the fundamental and resilient nature of the other to produce and reproduce the state of "post-Soviet limbo". We use the "post-Soviet limbo" as an overall framework aimed at conceptualizing the post-Soviet transformation as a combination of efforts to avoid and manage the uncertainty of TB treatment, especially in prison. We examine the empirical case of coerced mobility of prisoners who require TB treatment, seeking to trace how this process is reflected in the e-TB Manager. We provide a more in-depth picture of this journey with details gathered from qualitative research materials to situate numbers and variables in their contexts, deconstructing the way the data are recorded according to the logic of the system in which they are produced.

Agent-based models under uncertainty.

Background: Monte Carlo (MC) is often used when trying to assess the consequences of uncertainty in agent-based models (ABMs). However, this approach is not appropriate when the uncertainty is epistemic rather than aleatory, that is, when it represents a lack of knowledge rather than variation. The free-for-all battleship simulation modelled here is inspired by the children's battleship game, where each battleship is an agent. Methods: The models contrast an MC implementation against an interval implementation for epistemic uncertainty. In this case, our epistemic uncertainty is in the form of an imperfect radar. In the interval method, the approach occludes the status of the agents (ships) and precludes an analyst from making decisions about them in real-time. Results: In a highly uncertain environment, after many time steps, there can be many ships remaining whose status is unknown. In contrast, any MC simulation invariably tends to conclude with a small number of the remaining ships after many time steps. Thus, the interval approach misses the quantitative conclusion. However, some quantitative results are generated by the interval implementation, e.g. the identities of the surviving ships, which are revealed to be nearly mutual with the MC implementation, though with fewer identities in total compared to MC. Conclusions: We have demonstrated that it is possible to implement intervals in an ABM, but the results are broad, which may be useful for generating the overall bounds of the system but do not provide insight on the expected outcomes and trends.

[11C]CHDI-626, a PET Tracer Candidate for Imaging Mutant Huntingtin Aggregates with Reduced Binding to AD Pathological Proteins.

The expanded polyglutamine-containing mutant huntingtin (mHTT) protein is implicated in neuronal degeneration of medium spiny neurons in Huntington's disease (HD) for which multiple therapeutic approaches are currently being evaluated to eliminate or reduce mHTT. Development of effective and orthogonal biomarkers will ensure accurate assessment of the safety and efficacy of pharmacologic interventions. We have identified and optimized a class of ligands that bind to oligomerized/aggregated mHTT, which is a hallmark in the HD postmortem brain. These ligands are potentially useful imaging biomarkers for HD therapeutic development in both preclinical and clinical settings. We describe here the optimization of the benzo[4,5]imidazo[1,2-a]pyrimidine series that show selective binding to mHTT aggregates over Aß- and/or tau-aggregates associated with Alzheimer's disease pathology. Compound [11C]-2 was selected as a clinical candidate based on its high free fraction in the brain, specific binding in the HD mouse model, and rapid brain uptake/washout in nonhuman primate positron emission tomography imaging studies.

Cowper's Glands Abscess with Spreading to Adjacent Organs and Tissues with Development of Septic Shock: An Extremely Rare Case.

BACKGROUND: We present here the first case of Cowper's gland abscess complicated by septic shock and breakthrough of the abscess into the paraurethral region, cavernous body, scrotum, and pararectal tissue. CASE PRESENTATION: A 63-year-old patient was admitted with complaints of temperature increase up to 39°C, pain and enlargement of the perineum and the right half of the scrotum, frequent and difficulty urination, weakness, dizziness, dry mouth, and a sharp deterioration of the general condition. Clinical-laboratory data showed the presence of septic shock with unstable haemodynamics and many concomitant diseases. From the history, it is known that the patient for more than 20 years suffered from urinary tract infection and urinary disorders. Six months earlier, the patient underwent a puncture of a bulbourethral abscess. According to the ultrasound of the scrotum, TRUS, and MRI, bulbourethral abscess with spread to the right half of the scrotum, a part of the cavernous body, and the cellular tissue of the left sciatic-rectal fossa was diagnosed. Purulent cavities were opened with two incisions and drained. A cystostomy was installed. In the intensive care unit, according to a microbiological study (Escherichia coli, Klebsiella pneumoniae, and Klebsiella pneumoniae), antibacterial, detoxification, and symptomatic therapy of concomitant diseases were carried out together with a resuscitator and therapist. The patient was discharged on the 30th day with a negative analysis of urine culture, with a cystostomy, which was removed six months after the independent restoration of urination and closure of the fistulous passage between the urethra and Cowper's glands. CONCLUSION: Untimely treatment of the very rare abscess of the Cowper's gland can lead to serious complications, up to the spread of a purulent process to neighbouring organs and tissues, and the development of septic shock, which will require urgent and intensive therapy with the involvement of experts from interdisciplinary fields.

Correction: Is no test better than a bad test: Impact of diagnostic uncertainty on the spread of COVID-19.

[This corrects the article DOI: 10.1371/journal.pone.0240775.].

More evidence or stronger political will: exploring the feasibility of needle and syringe programs in Ukrainian prisons.

INTRODUCTION: In 2007, the World Health Organization (WHO) recommended for prison authorities to introduce prison needle and syringe programs (PNSP) if they have any evidence that injecting drug use is taking place in prisons. This article presents descriptive evidence that injecting drug use takes place in Ukrainian prisons, it discusses how (denial of) access to injection equipment is regulated in the current system and what changes should be considered in order to implement PNSP. BACKGROUND: Ukrainian prisons still live by the laws and policies adopted in the Soviet Union. Besides laws and regulations, these legacies are replicated through the organization and infrastructure of the prison's physical space, and through "carceral collectivism" as a specific form of living and behaving. Inviolability of the prison order over time helps the prison staff to normalize and routinely rationalize punishment enforcement as a power "over" prisoners, but not a power "for" achieving a specific goal. METHODS: The Participatory Action Research approach was used as a way of involving different actors in the study's working group and research process. The data were gathered through 160 semi-structured interviews with prison health care workers, guards, people who inject drugs (PWID) who served one or several terms and other informants. RESULTS: The "expertise" in drug use among prisoners demonstrated by prison staff tells us two things-they admit that injecting use takes place in prisons, and that the surveillance of prisoner behavior has been carried out constantly since the very beginning as a core function of control. The communal living conditions and prison collectivism may not only produce and reproduce a criminal subculture but, using the same mechanisms, produce and reproduce drug use in prison. The "political will" incorporated into prison laws and policies is essential for the revision of outdated legacies and making PNSP implementation feasible. CONCLUSION: PNSP implementation is not just a question of having evidence of injecting drug use in the hands of prison authorities. For PNSP to be feasible in the prison environment, there is a need for specific changes to transition from one historical period and political leadership to another. And, thus, to make PNSP work requires making power work for change, and not just for reproducing the power itself.

Is "no test is better than a bad test"? Impact of diagnostic uncertainty in mass testing on the spread of COVID-19.

Testing is viewed as a critical aspect of any strategy to tackle epidemics. Much of the dialogue around testing has concentrated on how countries can scale up capacity, but the uncertainty in testing has not received nearly as much attention beyond asking if a test is accurate enough to be used. Even for highly accurate tests, false positives and false negatives will accumulate as mass testing strategies are employed under pressure, and these misdiagnoses could have major implications on the ability of governments to suppress the virus. The present analysis uses a modified SIR model to understand the implication and magnitude of misdiagnosis in the context of ending lockdown measures. The results indicate that increased testing capacity alone will not provide a solution to lockdown measures. The progression of the epidemic and peak infections is shown to depend heavily on test characteristics, test targeting, and prevalence of the infection. Antibody based immunity passports are rejected as a solution to ending lockdown, as they can put the population at risk if poorly targeted. Similarly, mass screening for active viral infection may only be beneficial if it can be sufficiently well targeted, otherwise reliance on this approach for protection of the population can again put them at risk. A well targeted active viral test combined with a slow release rate is a viable strategy for continuous suppression of the virus.

Imaging Mutant Huntingtin Aggregates: Development of a Potential PET Ligand.

Mutant huntingtin (mHTT) protein carrying the elongated N-terminal polyglutamine (polyQ) tract misfolds and forms protein aggregates characteristic of Huntington's disease (HD) pathology. A high-affinity ligand specific for mHTT aggregates could serve as a positron emission tomography (PET) imaging biomarker for HD therapeutic development and disease progression. To identify such compounds with binding affinity for polyQ aggregates, we embarked on systematic structural activity studies; lead optimization of aggregate-binding affinity, unbound fractions in brain, permeability, and low efflux culminated in the discovery of compound 1, which exhibited target engagement in autoradiography (ARG) studies in brain slices from HD mouse models and postmortem human HD samples. PET imaging studies with 11C-labeled 1 in both HD mice and WT nonhuman primates (NHPs) demonstrated that the right-hand-side labeled ligand [11C]-1R (CHDI-180R) is a suitable PET tracer for imaging of mHTT aggregates. [11C]-1R is now being advanced to human trials as a first-in-class HD PET radiotracer.

Autoradiographic mapping of synaptic vesicle glycoprotein 2A in non-human primate and human brain.

Synaptic vesicle glycoprotein 2A (SV2A) has been previously characterized as an imaging biomarker for assessment of synaptic density in positron emission tomography (PET) studies of patients with neurological conditions. To provide detailed maps of the brain localization of SV2A autoradiography studies were carried out using the SV2A radioligand [11 C]UCB-J and whole hemisphere sections of non-human primate (NHP) and human brain. Binding of [11 C]UCB-J was observed in all evaluated grey matter structures of the primate brain, with highest density in the caudate nucleus and cortex and lowest density in pons and globus pallidus. The density of [11 C]UCB-J binding sites in human brain showed a good correlation with that in NHP brain. Binding of [11 C]UCB-J in the white matter was very low relative to that in grey matter containing structures and was only inhibited to a minor extent by co-incubation with a saturating concentration of unlabelled UCB-J. The high-resolution images obtained in the present study may aid the interpretation of data acquired in human subjects examined using [11 C]UCB-J in PET studies. In addition, observation of low binding for [11 C]UCB-J in white matter (centrum semiovale) supports that this structure can be used as a reference region for quantitative analysis of [11 C]UCB-J PET data.

PET imaging of beta-secretase 1 in the human brain: radiation dosimetry, quantification, and test-retest examination of [18F]PF-06684511.

PURPOSE: Beta-secretase 1 (BACE1) enzyme is implicated in the pathophysiology of Alzheimer's disease. [18F]PF-06684511 is a positron emission tomography (PET) radioligand for imaging BACE1. Despite favorable brain kinetic properties, the effective dose (ED) of [18F]PF-06684511 estimated in non-human primates was relatively high. This study was therefore designed to evaluate the whole-body distribution, dosimetry, quantification, and test-retest reliability of imaging brain BACE1 with [18F]PF-06684511 in healthy volunteers. METHODS: Five subjects were studied for the dosimetry study. Whole-body PET was performed for 366 min with 4 PET-CT sessions. Estimates of the absorbed radiation dose were calculated using the male adult model. Eight subjects participated in the test-retest study. Brain PET measurements were conducted for 123 min with an interval of 5 to 19 days between test and retest conditions. The total distribution volume (VT) was estimated with one-tissue (1T), two-tissue (2T), compartment model (CM), and graphical analysis. Test-retest variability (TRV) and intraclass correlation coefficient (ICC) of VT were calculated as reliability measures. RESULTS: In the dosimetry study, the highest uptake was found in the liver (25.2 ± 2.3 %ID at 0.5 h) and the largest dose was observed in the pancreas (92.9 ± 52.2 µSv/MBq). The calculated ED was 24.7 ± 0.8 µSv/MBq. In the test-retest study, 2TCM described the time-activity curves well. VT (2TCM) was the highest in the anterior cingulate cortex (6.28 ± 1.09 and 6.85 ± 0.81) and the lowest in the cerebellum (4.23 ± 0.88 and 4.20 ± 0.75). Mean TRV and ICC of VT (2TCM) were 16.5% (12.4-20.5%) and 0.496 (0.291-0.644). CONCLUSION: The ED of [18F]PF-06684511 was similar to other 18F radioligands, allowing repeated PET measurements. 2TCM was the most appropriate quantification method. TRV of VT was similar to other radioligands without a reference region, albeit with lower ICC. These data indicated that [18F]PF-06684511 is a suitable radioligand to measure BACE1 level in the human brain. TRIAL REGISTRATION: EudraCT 2016-001110-19 (registered 2016-08-08).

The pro-psychotic metabotropic glutamate receptor compounds fenobam and AZD9272 share binding sites with monoamine oxidase-B inhibitors in humans.

The metabotropic glutamate receptor 5 (mGluR5) ligands fenobam and AZD9272 have been reported to induce psychosis-like adverse events and to bind at unknown, non-GluR5-related, sites. Based on similarities of the regional binding patterns for [11C]AZD9272 and the monoamine oxidase-B (MAO-B) radioligand [11C]L-deprenyl-D2 in PET studies of the human brain we tested the hypothesis that the unique binding of fenobam and AZD9272 may represent specific binding to the MAO-B. PET data previously acquired for subjects examined using [11C]AZD9272 or [11C]L-deprenyl-D2 were re-evaluated to assess the correlations between radioligand binding parameters in human brain. In addition, the pharmacology of AZD9272 binding sites was characterized using competition binding studies carried out in vivo in non-human primates (NHPs) and in vitro using autoradiography in selected human brain regions. The regional binding of [11C]AZD9272 in human brain was closely correlated with that of [11C]L-deprenyl-D2. In PET studies of NHP brain administration of the MAO-B ligand L-deprenyl inhibited binding of radiolabeled AZD9272 and administration of fenobam inhibited binding of [11C]L-deprenyl-D2. Binding of radiolabeled AZD9272 in vitro was potently inhibited by fenobam or MAO-B compounds, and [11C]L-deprenyl-D2 binding was inhibited by fenobam or AZD9272. The findings are consistent with the hypothesis that both fenobam and AZD9272 bind to the MAO-B, which may be of relevance for understanding the mechanism of the psychosis-like adverse events reported for these compounds. Such understanding may serve as a lead to generate new models for the pathophysiology of psychosis.

Effect of clinically relevant doses of vortioxetine and citalopram on serotonergic PET markers in the nonhuman primate brain.

Vortioxetine is a multimodal antidepressant approved for treatment of major depressive disorder. Preclinical studies have demonstrated that the mechanism of action of vortioxetine might be different from selective serotonin reuptake inhibitors (SSRIs), including larger serotonin (5-HT) release and direct modulation of several 5-HT receptors. In the current positron emission tomography (PET) study, we evaluated the mechanism of action of vortioxetine by comparing its effect to the SSRI citalopram on the binding of [11C]AZ10419369 to the 5-HT1B receptor in the nonhuman primate brain. Initially, the 5-HT transporter (5-HTT) binding of vortioxetine was determined by [11C]MADAM PET measurements before and after administration of vortioxetine (0.1-3.0 mg/kg) and data were used to confirm clinically relevant dosing in subsequent PET measurements with [11C]AZ10419369. The 5-HT1B receptor binding was significantly decreased after 0.3 mg/kg of citalopram in the dorsal raphe nucleus (5%), as well as after 0.3 mg/kg of vortioxetine in six brain regions (~25%) or 1.0 mg/kg of vortioxetine in all 12 examined regions (~48%). Moreover, there was no effect of 1.0 mg/kg of vortioxetine on the binding of [11C]Cimbi-36 to the 5-HT2A receptor, which has comparable sensitivity to 5-HT release as [11C]AZ10419369 binding. In conclusion, at clinically relevant doses, vortioxetine induced larger reductions in [11C]AZ10419369 binding than citalopram. These observations suggest that vortioxetine binds to the 5-HT1B receptor at clinically relevant doses. Future studies are warranted to evaluate the role of the 5-HT1B receptor in the therapeutic effects of vortioxetine and as a potential target for the development of novel antidepressant drugs.

Performance indicator as the main and the only goal: a "dark side" of the intervention aims to accelerate HIV treatment entry among people who inject drugs in Kyiv, Ukraine.

BACKGROUND: To improve healthcare entry and antiretroviral therapy (ART) initiation for HIV-positive people who inject drugs (PWID) in Ukraine, an intervention built upon a successful community-based harm reduction project and the existing best practices was developed. In this article, we present the results of the study conducted in collaboration with one of the recipient organizations of the intervention in Kyiv. The research question was formulated as follows: how does the interaction between different actors work to lead it to a positive outcome (initiation PWIDs into ART) within the limited period of the intervention implementation? METHODS: The central focus of the study was on the work activities of case managers. Their daily routines as well as their interactions with their clients and medical workers were observed and analyzed. Using the institutional ethnography approach, we explore the institutional orders, power imbalances, and social factors that play different roles in coordinating the process of PWIDs entry into healthcare and HIV treatment. RESULTS: The most intriguing result of the study is that the performance indicator that must be completed in order to receive a full salary-as a way to manage the activities of case managers-produces conditions for them to develop their cooperation with medical workers but leaves the clients and their needs out of this "boat" because interaction with them, in fact, does not help to meet case managers' goals. CONCLUSIONS: Accountability of case managers' work assumes the primacy of the result over the process, which makes the process itself less important and the need to achieve the goal becomes the main and the only goal. This can be identified as an unintended consequence of the intervention implementation on the ground, or wider-an unintended consequence of the payment by results practice as a part of the general number-based policy.

Dual tracer tau PET imaging reveals different molecular targets for 11C-THK5351 and 11C-PBB3 in the Alzheimer brain.

PURPOSE: Several tau PET tracers have been developed, but it remains unclear whether they bind to the same molecular target on the heterogeneous tau pathology. In this study we evaluated the binding of two chemically different tau-specific PET tracers (11C-THK5351 and 11C-PBB3) in a head-to-head, in vivo, multimodal design. METHODS: Nine patients with a diagnosis of mild cognitive impairment or probable Alzheimer's disease and cerebrospinal fluid biomarker evidence supportive of the presence of Alzheimer's disease brain pathology were recruited after thorough clinical assessment. All patients underwent imaging with the tau-specific PET tracers 11C-THK5351 and 11C-PBB3 on the same day, as well as imaging with the amyloid-beta-specific tracer 11C-AZD2184, a T1-MRI sequence, and neuropsychological assessment. RESULTS: The load and regional distribution of binding differed between 11C-THK5351 and 11C-PBB3 with no statistically significant regional correlations observed between the tracers. The binding pattern of 11C-PBB3, but not that of 11C-THK5351, in the temporal lobe resembled that of 11C-AZD2184, with strong correlations detected between 11C-PBB3 and 11C-AZD2184 in the temporal and occipital lobes. Global cognition correlated more closely with 11C-THK5351 than with 11C-PBB3 binding. Similarly, cerebrospinal fluid tau measures and entorhinal cortex thickness were more closely correlated with 11C-THK5351 than with 11C-PBB3 binding. CONCLUSION: This research suggests different molecular targets for these tracers; while 11C-PBB3 appeared to preferentially bind to tau deposits with a close spatial relationship to amyloid-beta, the binding pattern of 11C-THK5351 fitted the expected distribution of tau pathology in Alzheimer's disease better and was more closely related to downstream disease markers.

The metabotropic glutamate receptor 5 radioligand [11C]AZD9272 identifies unique binding sites in primate brain.

The metabotropic glutamate receptor 5 (mGluR5) is a target for drug development and for imaging studies of the glutamate system in neurological and psychiatric disorders. [11C]AZD9272 is a selective mGluR5 PET radioligand that is structurally different from hitherto applied mGluR5 radioligands. In the present investigation we compared the binding patterns of radiolabeled AZD9272 and other mGluR5 radioligands in the non-human primate (NHP) brain. PET studies were undertaken using [11C]AZD9272 and the commonly applied mGluR5 radioligand [11C]ABP688. Autoradiography studies were performed in vitro using [3H]AZD9272 and the standard mGluR5 radioligands [3H]M-MTEP and [3H]ABP688 in NHP tissue. Competition binding studies were undertaken in vivo and in vitro using different mGluR5 selective compounds as inhibitors. In comparison to other mGluR5 radioligands radiolabeled AZD9272 displayed a distinct regional distribution pattern with high binding in ventral striatum, midbrain, thalamus and cerebellum. While the binding of [11C]AZD9272 was almost completely inhibited by the structurally unique mGluR5 compound fenobam (2.0 mg/kg; 98% occupancy), it was only partially inhibited (46% and 20%, respectively) by the mGluR5 selective compounds ABP688 and MTEP, at a dose (2.0 mg/kg) expected to saturate the mGluR5. Autoradiography studies using [3H]AZD9272 confirmed a distinct pharmacologic profile characterized by preferential sensitivity to fenobam. The distinctive binding in ventral striato-pallido-thalamic circuits and shared pharmacologic profile with the pro-psychotic compound fenobam warrants further examination of [11C]AZD9272 for potential application in psychiatric neuroimaging studies.

Development of two fluorine-18 labeled PET radioligands targeting PDE10A and in vivo PET evaluation in nonhuman primates.

INTRODUCTION: Phosphodiesterase 10A (PDE10A) is a member of the PDE enzyme family that degrades cyclic adenosine and guanosine monophosphates (cAMP and cGMP). Based on the successful development of [11C]T-773 as PDE10A positron emission tomography (PET) radioligand, in this study our aim was to develop and evaluate fluorine-18 analogs of [11C]T-773. METHODS: [18F]FM-T-773-d2 and [18F]FE-T-773-d4 were synthesized from the same precursor used for 11C-labeling of T-773 in a two-step approach via 18F-fluoromethylation and 18F-fluoroethylation, respectively, using corresponding deuterated synthons. A total of 12 PET measurements were performed in seven non-human primates. First, baseline PET measurements were performed using High Resolution Research Tomograph system with both [18F]FM-T-773-d2 and [18F]FE-T-773-d4; the uptake in whole brain and separate brain regions, as well as the specific binding and tissue ratio between putamen and cerebellum, was examined. Second, baseline and pretreatment PET measurements using MP-10 as the blocker were performed for [18F]FM-T-773-d2 including arterial blood sampling with radiometabolite analysis in four NHPs. RESULTS: Both [18F]FM-T-773-d2 and [18F]FE-T-773-d4 were successfully radiolabeled with an average molar activity of 293 ± 114 GBq/µmol (n=8) for [18F]FM-T-773-d2 and 209 ± 26 GBq/µmol (n=4) for [18F]FE-T-773-d4, and a radiochemical yield of 10% (EOB, n=12, range 3%-16%). Both radioligands displayed high brain uptake (~5.5% of injected radioactivity for [18F]FM-T-773-d2 and ~3.5% for [18F]FE-T-773-d4 at the peak) and a fast washout. Specific binding reached maximum within 30 min for [18F]FM-T-773-d2 and after approximately 45 min for [18F]FE-T-773-d4. [18F]FM-T-773-d2 data fitted well with kinetic compartment models. BPND values obtained indirectly through compartment models were correlated well with those obtained by SRTM. BPND calculated with SRTM was 1.0-1.7 in the putamen. The occupancy with 1.8 mg/kg of MP-10 was approximately 60%. CONCLUSIONS: [18F]FM-T-773-d2 and [18F]FE-T-773-d4 were developed as fluorine-18 PET radioligands for PDE10A, with the [18F]FM-T-773-d2 being the more promising PET radioligand warranting further evaluation.

Comparative binding properties of the tau PET tracers THK5117, THK5351, PBB3, and T807 in postmortem Alzheimer brains.

BACKGROUND: The aim of this study was to compare the binding properties of several tau positron emission tomography tracers-THK5117, THK5351, T807 (also known as AV1451; flortaucipir), and PBB3-head to head in the same human brain tissue. METHODS: Binding assays were performed to compare the regional distribution of 3H-THK5117 and 3H-THK5351 in postmortem tissue from three Alzheimer's disease (AD) cases and three control subjects in frontal and temporal cortices as well as in the hippocampus. Competition binding assays between THK5351, THK5117, PBB3, and T807, as well as off-target binding of THK5117 and T807 toward monoamine oxidase B (MAO-B), were performed using binding assays in brain homogenates and autoradiography of three AD cases. RESULTS: Regional binding of 3H-THK5117 and 3H-THK5351 was similar, except in the temporal cortex, which showed higher 3H-THK5117 binding. Saturation studies demonstrated two binding sites for 3H-THK5351 (K d1 = 5.6 nM, Bmax = 76 pmol/g; K d2 = 1 nM, Bmax = 40 pmol/g). Competition studies in the hippocampus between 3H-THK5351 and unlabeled THK5351, THK5117, and T807 revealed super-high-affinity sites for all three tracers (THK5351 K i = 0.1 pM; THK5117 K i = 0.3 pM; T807 K i = 0.2 pM) and an additional high-affinity site (THK5351 K i = 16 nM; THK5117 K i = 20 nM; T807 K i = 78nM). 18F-T807, 11C-THK5351, and 11C-PBB3 autoradiography of large frozen sections from three AD brains showed similar regional binding for the three tracers, with lower binding intensity for 11C-PBB3. Unlabeled THK5351 and T807 displaced 11C-THK5351 to a similar extent and a lower extent, respectively, compared with 11C-PBB3. Competition with the MAO-B inhibitor 3H-L-deprenyl was observed for THK5117 and T807 in the hippocampus (THK5117 K i = 286 nM; T807 K i = 227 nM) and the putamen (THK5117 K i = 148 nM; T807 K i = 135 nM). 3H-THK5351 binding was displaced using autoradiography competition with unlabeled THK5351 and T807 in cortical areas by 70-80% and 60-77%, respectively, in the basal ganglia, whereas unlabeled deprenyl displaced 3H-THK5351 binding by 40% in the frontal cortex and 50% in the basal ganglia. CONCLUSIONS: THK5351, THK5117, and T807 seem to target similar binding sites, but with different affinities, whereas PBB3 seems to target its own binding site. Both THK5117 and T807 demonstrated off-target binding in the hippocampus and putamen with a ten times lower binding affinity to the MAO-B inhibitor deprenyl compared with 3H-THK5351.

Fenfluramine Reduces [11C]Cimbi-36 Binding to the 5-HT2A Receptor in the Nonhuman Primate Brain.

Background: [11C]Cimbi-36 is a serotonin 2A receptor agonist positron emission tomography radioligand that has recently been examined in humans. The binding of agonist radioligand is expected to be more sensitive to endogenous neurotransmitter concentrations than antagonist radioligands. In the current study, we compared the effect of serotonin releaser fenfluramine on the binding of [11C]Cimbi-36, [11C]MDL 100907 (a serotonin 2A receptor antagonist radioligand), and [11C]AZ10419369 (a serotonin 1B receptor partial agonist radioligand with established serotonin sensitivity) in the monkey brain. Methods: Eighteen positron emission tomography measurements, 6 for each radioligand, were performed in 3 rhesus monkeys before or after administration of 5.0 mg/kg fenfluramine. Binding potential values were determined with the simplified reference tissue model using cerebellum as the reference region. Results: Fenfluramine significantly decreased [11C]Cimbi-36 (26-62%) and [11C]AZ10419369 (35-58%) binding potential values in most regions (P < 0.05). Fenfluramine-induced decreases in [11C]MDL 100907 binding potential were 8% to 30% and statistically significant in 3 regions. Decreases in [11C]Cimbi-36 binding potential were larger than for [11C]AZ10419369 in neocortical and limbic regions (~35%) but smaller in striatum and thalamus (~40%). Decreases in [11C]Cimbi-36 binding potential were 0.9 to 2.8 times larger than for [11C]MDL 100907, and the fraction of serotonin 2A receptor in the high-affinity state was estimated as 54% in the neocortex. Conclusions: The serotonin sensitivity of serotonin 2A receptor agonist radioligand [11C]Cimbi-36 was higher than for antagonist radioligand [11C]MDL 100907. The serotonin sensitivity of [11C]Cimbi-36 was similar to [11C]AZ10419369, which is one of the most sensitive radioligands. [11C]Cimbi-36 is a promising radioligand to examine serotonin release in the primate brain.

Development of [11C]/[3H]THK-5351 - A potential novel carbon-11 tau imaging PET radioligand.

INTRODUCTION: Due to the rise in the number of patients with dementia the imperative for finding new diagnostic and treatment options becomes ever more pressing. While significant progress has been made in PET imaging of Aß aggregates both in vitro and in vivo, options for imaging tau protein aggregates selectively are still limited. Based on the work previously published by researchers from the Tohoku University, Japan, that resulted in the development of [18F]THK-5351, we have undertaken an effort to develop a carbon-11 version of the identical structure - [11C]THK-5351. In parallel, THK-5351 was also labeled with tritium ([3H]THK-5351) for use in in vitro autoradiography (ARG). METHODS: The carbon-11 labeling was performed starting with di-protected enantiomeric pure precursor - tert-butyl 5-(6-((2S)-3-fluoro-2-(tetrahydro-2H-pyran-2-yloxy)propoxy)quinolin-2-yl)pyridin-2-yl carbamate, which was reacted with [11C]MeI, using DMF as the solvent and NaH as base, followed by deprotection with trifluoroacetic acid/water mixture, resulting in enantiomerically pure carbon-11 radioligand, [11C]THK-5351 - (S)-1-fluoro-3-(2-(6-([11C]methylamino)pyridin-3-yl)quinolin-6-yloxy)propan-2-ol. Tritium labeling and purification of [3H]THK-5351 were undertaken using similar approach, resulting in [3H]THK-5351 with RCP >99.8% and specific radioactivity of 1.3GBq/µmol. RESULTS: [11C]THK-5351 was produced in good yield (1900±355MBq), specific radioactivity (SRA) (361±119GBq/µmol at EOS+20min) and radiochemical purity (RCP) (>99.8%), with enantiomeric purity of 98.7%. [3H]THK-5351 was evaluated for ARG of tau binding in post-mortem human brain tissue using cortical sections from one AD patient and one control subject. [3H]THK-5351 binding density was higher in the AD patient compared to the control subject, the binding was displaced by unlabeled THK-5351 confirming specific [3H]THK-5351 binding.

Characterization of [11C]Lu AE92686 as a PET radioligand for phosphodiesterase 10A in the nonhuman primate brain.

PURPOSE: [11C]Lu AE92686 is a positron emission tomography (PET) radioligand that has recently been validated for examining phosphodiesterase 10A (PDE10A) in the human striatum. [11C]Lu AE92686 has high affinity for PDE10A (IC 50 = 0.39 nM) and may also be suitable for examination of the substantia nigra, a region with low density of PDE10A. Here, we report characterization of regional [11C]Lu AE92686 binding to PDE10A in the nonhuman primate (NHP) brain. METHODS: A total of 11 PET measurements, seven baseline and four following pretreatment with unlabeled Lu AE92686 or the structurally unrelated PDE10A inhibitor MP-10, were performed in five NHPs using a high resolution research tomograph (HRRT). [11C]Lu AE92686 binding was quantified using a radiometabolite-corrected arterial input function and compartmental and graphical modeling approaches. RESULTS: Regional time-activity curves were best described with the two-tissue compartment model (2TCM). However, the distribution volume (V T) values for all regions were obtained by the Logan plot analysis, as reliable cerebellar V T values could not be derived by the 2TCM. For cerebellum, a proposed reference region, V T values increased by ∼30 % with increasing PET measurement duration from 63 to 123 min, while V T values in target regions remained stable. Both pretreatment drugs significantly decreased [11C]Lu AE92686 binding in target regions, while no significant effect on cerebellum was observed. Binding potential (BP ND) values, derived with the simplified reference tissue model (SRTM), were 13-17 in putamen and 3-5 in substantia nigra and correlated well to values from the Logan plot analysis. CONCLUSIONS: The method proposed for quantification of [11C]Lu AE92686 binding in applied studies in NHP is based on 63 min PET data and SRTM with cerebellum as a reference region. The study supports that [11C]Lu AE92686 can be used for PET examinations of PDE10A binding also in substantia nigra.