Adaptive algorithms for shaping behavior.

Dogs and laboratory mice are commonly trained to perform complex tasks by guiding them through a curriculum of simpler tasks ('shaping'). What are the principles behind effective shaping strategies? Here, we propose a machine learning framework for shaping animal behavior, where an autonomous teacher agent decides its student's task based on the student's transcript of successes and failures on previously assigned tasks. Using autonomous teachers that plan a curriculum in a common sequence learning task, we show that near-optimal shaping algorithms adaptively alternate between simpler and harder tasks to carefully balance reinforcement and extinction. Based on this intuition, we derive an adaptive shaping heuristic with minimal parameters, which we show is near-optimal on the sequence learning task and robustly trains deep reinforcement learning agents on navigation tasks that involve sparse, delayed rewards. Extensions to continuous curricula are explored. Our work provides a starting point towards a general computational framework for shaping animal behavior.

Neural Circuits for Fast Poisson Compressed Sensing in the Olfactory Bulb.

Within a single sniff, the mammalian olfactory system can decode the identity and concentration of odorants wafted on turbulent plumes of air. Yet, it must do so given access only to the noisy, dimensionally-reduced representation of the odor world provided by olfactory receptor neurons. As a result, the olfactory system must solve a compressed sensing problem, relying on the fact that only a handful of the millions of possible odorants are present in a given scene. Inspired by this principle, past works have proposed normative compressed sensing models for olfactory decoding. However, these models have not captured the unique anatomy and physiology of the olfactory bulb, nor have they shown that sensing can be achieved within the 100-millisecond timescale of a single sniff. Here, we propose a rate-based Poisson compressed sensing circuit model for the olfactory bulb. This model maps onto the neuron classes of the olfactory bulb, and recapitulates salient features of their connectivity and physiology. For circuit sizes comparable to the human olfactory bulb, we show that this model can accurately detect tens of odors within the timescale of a single sniff. We also show that this model can perform Bayesian posterior sampling for accurate uncertainty estimation. Fast inference is possible only if the geometry of the neural code is chosen to match receptor properties, yielding a distributed neural code that is not axis-aligned to individual odor identities. Our results illustrate how normative modeling can help us map function onto specific neural circuits to generate new hypotheses.

Ultrasensitive Detection and Separation of Pancreatic Cancer Biomarker CA 19-9 Using a Multiphoton Laser Wave-Mixing Detector Interfaced to Capillary Electrophoresis.

The carbohydrate antigen 19-9 (CA 19-9) is the most commonly used biomarker in the clinical diagnosis of pancreatic cancer. Multiphoton nonlinear laser wave-mixing spectroscopy is presented as an ultrasensitive detection method for CA 19-9. Wave mixing is an optical absorption-based method, and hence, one can detect CA 19-9 without labels in their native form using compact ultraviolet (UV) lasers or labeled samples using a visible laser. The wave-mixing signal exhibits a quadratic dependence on the sample concentration, and hence, it is an ideal sensor to monitor small changes in the sample. Wave mixing has inherent advantages over other absorption-based detection methods, including short optical path length (micrometer-thin samples instead of 1 cm cuvette) and excellent spatial resolution (micrometer probe). Since the laser wave-mixing probe volume is small (picoliter), it is convenient to interface to microfluidics or capillary-based electrophoresis systems to enhance chemical specificity. Our wave-mixing detectors could be configured as portable battery-powered devices suitable for field use. Laser wave-mixing spectroscopy offers enhanced selectivity levels for protein detection when coupled with capillary electrophoresis (CE). We report a concentration detection limit of 0.16 U/mL, and a corresponding mass detection limit of 1.2 × 10-8 U, and these detection limits are better than those of chemiluminescence- or ELISA- based methods.

Sensitive detection of heart-failure biomarkers natriuretic peptides using multi-photon laser wave-mixing spectroscopy.

Nonlinear laser wave-mixing spectroscopy is demonstrated as a fast and sensitive detection method for heart-failure biomarkers, pro-atrial natriuretic peptide (proANP) and brain natriuretic peptide (BNP). Wave mixing is an ultrasensitive optical absorption-based method and analytes can be detected in their native form or labeled with fluorophore and chromophore labels. In this study, we utilized Chromeo P540 dye to label the peptides for wave-mixing detection. The wave-mixing signal is created from the diffraction of incoming photons by the thermal grating at the capillary analyte cell. The signal beam is strong, collimated, and coherent (laser-like) and it is collected using a simple photodetector with an excellent signal-to-noise ratio. We demonstrated advantages of this technique over conventional assays including shorter analysis times, smaller sample requirements, and higher throughput. To enhance detection selectivity and sensitivity levels, wave mixing is effectively coupled to capillary zone electrophoresis (CZE) and field-amplified sample stacking (FASS) methods. We determined detection limits of 7.4 × 10-10 M or 55 zmol and 6.8 × 10-10 M or 51 zmol for proANP and BNP, respectively, and separated and detected both peptides within 2 min. Due to the challenges in the confirmatory diagnoses of heart failure, wave-mixing serves as a potentially beneficial screening tool in addition to the commonly used echocardiographic tests.

Contrasting random and learned features in deep Bayesian linear regression.

Understanding how feature learning affects generalization is among the foremost goals of modern deep learning theory. Here, we study how the ability to learn representations affects the generalization performance of a simple class of models: deep Bayesian linear neural networks trained on unstructured Gaussian data. By comparing deep random feature models to deep networks in which all layers are trained, we provide a detailed characterization of the interplay between width, depth, data density, and prior mismatch. We show that both models display samplewise double-descent behavior in the presence of label noise. Random feature models can also display modelwise double descent if there are narrow bottleneck layers, while deep networks do not show these divergences. Random feature models can have particular widths that are optimal for generalization at a given data density, while making neural networks as wide or as narrow as possible is always optimal. Moreover, we show that the leading-order correction to the kernel-limit learning curve cannot distinguish between random feature models and deep networks in which all layers are trained. Taken together, our findings begin to elucidate how architectural details affect generalization performance in this simple class of deep regression models.

Nonlinear Decoding of Natural Images From Large-Scale Primate Retinal Ganglion Recordings.

Decoding sensory stimuli from neural activity can provide insight into how the nervous system might interpret the physical environment, and facilitates the development of brain-machine interfaces. Nevertheless, the neural decoding problem remains a significant open challenge. Here, we present an efficient nonlinear decoding approach for inferring natural scene stimuli from the spiking activities of retinal ganglion cells (RGCs). Our approach uses neural networks to improve on existing decoders in both accuracy and scalability. Trained and validated on real retinal spike data from more than 1000 simultaneously recorded macaque RGC units, the decoder demonstrates the necessity of nonlinear computations for accurate decoding of the fine structures of visual stimuli. Specifically, high-pass spatial features of natural images can only be decoded using nonlinear techniques, while low-pass features can be extracted equally well by linear and nonlinear methods. Together, these results advance the state of the art in decoding natural stimuli from large populations of neurons.

In Vivo Evaluation of the Combined Anticancer Effects of Cisplatin and SAHA in Nonsmall Cell Lung Carcinoma Using [18F]FAHA and [18F]FDG PET/CT Imaging.

Combining standard drugs with low doses of histone deacetylase inhibitors (HDACIs) is a promising strategy to increase the efficacy of chemotherapy. The ability of well-tolerated doses of HDACIs that act as chemosensitizers for platinum-based chemotherapeutics has recently been proven in many types and stages of cancer in vitro and in vivo. Detection of changes in HDAC activity/expression may provide important prognostic and predictive information and influence treatment decision-making. Use of [18F] FAHA, a HDAC IIa-specific radionuclide, for molecular imaging may enable longitudinal, noninvasive assessment of HDAC activity/expression in metastatic cancer. We evaluated the synergistic anticancer effects of cisplatin and the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) in xenograft models of nonsmall cell lung cancer (NSCLC) using [18F] FAHA and [18F] FDG PET/CT imaging. Cisplatin alone significantly increased [18F] FAHA accumulation and reduced [18F] FDG accumulation in H441 and PC14 xenografts; coadministration of cisplatin and SAHA resulted in the opposite effects. Immunochemical staining for acetyl-histone H3 confirmed the PET/CT imaging findings. Moreover, SAHA had a more significant effect on the acetylome in PC14 (EGFR exon 19 deletion mutation) xenografts than H441 (wild-type EGFR and KRAS codon 12 mutant) xenografts. In conclusion, [18F] FAHA enables quantitative visualization of HDAC activity/expression in vivo, thus, may represent a clinically useful, noninvasive tool for the management of patients who may benefit from synergistic anticancer therapy.

The importance of porphyrins in blue light suppression of Streptococcus agalactiae.

It is well documented that blue light absorption by bacterial chromophores triggers downstream production of reactive oxygen species (ROS), which in turn results in bacterial cell death. To elucidate the importance of chromophores in the bactericidal effect of blue light, and to determine whether blue light absorption per se or the presence of porphyrins known to engender ROS is crucial in blue light treatment, we studied the effect of 450 nm pulsed light on Streptococcus agalactiae, also known as Group B Streptococcus (GBS) strain COH1. GBS does not synthesize porphyrins but has a blue light-absorbing chromophore, granadaene. We irradiated planktonic cultures of GBS with or without exogenous chromophore supplementation using either protoporphyrin IX (PPIX), coproporphyrin III (CPIII), Nicotinamide adenine dinucleotide (NAD), reduced nicotinamide adenine dinucleotide (NADH), Flavin adenine dinucleotide (FAD), or Flavin mononucleotide (FMN). Quantification of surviving bacterial colonies, presented as percent survival and CFU/mL (log10), showed that (1) 450 nm blue light does not suppress the growth of GBS, even though its endogenous chromophore, granadaene, absorbs light in the 450 nm spectrum. (2) The addition of either of the two exogenous porphyrins, PPIX or CPIII, significantly suppressed GBS, indicating the importance of porphyrins in the antimicrobial action of blue light. (3) Adding exogenous FMN or FAD, two known absorbers of 450 nm light, minimally potentiated the bactericidal effect of blue light, again confirming that mere absorption of blue light by chromophores does not necessarily result in bacterial suppression. (4) Irradiation of GBS with or without NAD+ or NADH supplementation-two weak absorbers of 450 nm light-minimally suppressed GBS, indicating that a blue light-absorbing chromophore is essential for the bactericidal action of blue light. (5) Collectively, these findings show that in addition to the presence of a blue light-absorbing chromophore in bacteria, a chromophore with the right metabolic machinery and biochemical structure, capable of producing ROS, is necessary for 450 nm blue light to suppress GBS.

Optimizing the bactericidal effect of pulsed blue light on Propionibacterium acnes - A correlative fluorescence spectroscopy study.

Propionibacterium acnes infection is the eighth most prevalent disease, affecting 80% of people worldwide. Resistance to antibiotics has been on the rise; over 40% of acne infections now resist commonly used topical and oral anti-acnes antibiotics, making treatment difficult. In our effort to refine blue light as an alternative safe clinically effective treatment, we determined if 100% bacterial suppression is attainable at ultralow irradiances and radiant energies, and explored the relationship between bacterial suppression and fluorescence during treatment. P. acnes were irradiated in vitro repeatedly three times per day at 3- or 4-hour intervals over three or more days, using 3 or 5 J/cm2 radiant energy of 450 nm pulsed blue light (PBL) at irradiances as low as 2 mW/cm2. In another series of experiments, we measured changes in P. acnes fluorescence as bacteria were repeatedly irradiated at various radiant exposures over three to four days. Our results showed that (1) 33% PBL, applied three times per day at 3-hour intervals each day over a three-day period at 2 mW/cm2 irradiance and 5 J/cm2 radiant exposure, resulted in100% bacterial suppression (7 log10 reduction), (2) the absorbed 450 nm light caused P. acnes to fluoresce predominantly in the red spectrum, with the fluorescence diminishing correlatively as treatment was repeated at 3-hour intervals and rising significantly during long periods of no treatment, and (3) treatment at 3-hour intervals gave better results than treatment at 4-hour intervals.

Efficacy of a Mobile Social Networking Intervention in Promoting Physical Activity: Quasi-Experimental Study.

BACKGROUND: Technological interventions such as mobile apps, Web-based social networks, and wearable trackers have the potential to influence physical activity; yet, only a few studies have examined the efficacy of an intervention bundle combining these different technologies. OBJECTIVE: This study aimed to pilot test an intervention composed of a social networking mobile app, connected with a wearable tracker, and investigate its efficacy in improving physical activity, as well as explore participant engagement and the usability of the app. METHODS: This was a pre-post quasi-experimental study with 1 arm, where participants were subjected to the intervention for a 6-month period. The primary outcome measure was the difference in daily step count between baseline and 6 months. Secondary outcome measures included engagement with the intervention and system usability. Descriptive and inferential statistical tests were conducted; posthoc subgroup analyses were carried out for participants with different levels of steps at baseline, app usage, and social features usage. RESULTS: A total of 55 participants were enrolled in the study; the mean age was 23.6 years and 28 (51%) were female. There was a nonstatistically significant increase in the average daily step count between baseline and 6 months (mean change=14.5 steps/day, P=.98, 95% CI -1136.5 to 1107.5). Subgroup analysis comparing the higher and lower physical activity groups at baseline showed that the latter had a statistically significantly higher increase in their daily step count (group difference in mean change from baseline to 6 months=3025 steps per day, P=.008, 95% CI 837.9-5211.8). At 6 months, the retention rate was 82% (45/55); app usage decreased over time. The mean system usability score was 60.1 (SD 19.2). CONCLUSIONS: This study showed the preliminary efficacy of a mobile social networking intervention, integrated with a wearable tracker to promote physical activity, particularly for less physically active subgroups of the population. Future research should explore how to address challenges faced by physically inactive people to provide tailored advices. In addition, users' perspectives should be explored to shed light on factors that might influence their engagement with the intervention.

Caspase-3 Substrates for Noninvasive Pharmacodynamic Imaging of Apoptosis by PET/CT.

Quantitative imaging of apoptosis in vivo could enable real-time monitoring of acute cell death pathologies such as traumatic brain injury, as well as the efficacy and safety of cancer therapy. Here, we describe the development and validation of F-18-labeled caspase-3 substrates for PET/CT imaging of apoptosis. Preliminary studies identified the O-benzylthreonine-containing substrate 2MP-TbD-AFC as a highly caspase 3-selective and cell-permeable fluorescent reporter. This lead compound was converted into the radiotracer [18F]-TBD, which was obtained at 10% decay-corrected yields with molar activities up to 149 GBq/µmol on an automated radiosynthesis platform. [18F]-TBD accumulated in ovarian cancer cells in a caspase- and cisplatin-dependent fashion. PET imaging of a Jo2-induced hepatotoxicity model showed a significant increase in [18F]-TBD signal in the livers of Jo2-treated mice compared to controls, driven through a reduction in hepatobiliary clearance. A chemical control tracer that could not be cleaved by caspase 3 showed no change in liver accumulation after induction of hepatocyte apoptosis. Our data demonstrate that [18F]-TBD provides an immediate pharmacodynamic readout of liver apoptosis in mice by dynamic PET/CT and suggest that [18F]-TBD could be used to interrogate apoptosis in other disease states.

In Vivo 6-([18F]Fluoroacetamido)-1-hexanoicanilide PET Imaging of Altered Histone Deacetylase Activity in Chemotherapy-Induced Neurotoxicity.

Background: Histone deacetylases (HDACs) regulate gene expression by changing histone deacetylation status. Neurotoxicity is one of the major side effects of cisplatin, which reacts with deoxyribonucleic acid (DNA) and has excellent antitumor effects. Suberoylanilide hydroxamic acid (SAHA) is an HDAC inhibitor with neuroprotective effects against cisplatin-induced neurotoxicity. Purpose: We investigated how cisplatin with and without SAHA pretreatment affects HDAC expression/activity in the brain by using 6-([18F]fluoroacetamido)-1-hexanoicanilide ([18F]FAHA) as a positron emission tomography (PET) imaging agent for HDAC IIa. Materials and Methods: [18F]FAHA and [18F]fluoro-2-deoxy-2-D-glucose ([18F]FDG) PET studies were done in 24 mice on 2 consecutive days and again 1 week later. The mice were divided into three groups according to drug administration between the first and second imaging sessions (Group A: cisplatin 2 mg/kg, twice; Group B: cisplatin 4 mg/kg, twice; Group C: cisplatin 4 mg/kg, twice, and SAHA 300 mg/kg pretreatment, 4 times). Results: The Ki value of [18F]FAHA was increased and the percentage of injected dose/tissue g (% ID/g) of [18F]FDG was decreased in the brains of animals in Groups A and B. The Ki value of [18F]FAHA and % ID/g of [18F]FDG were not significantly different in Group C. Conclusions: [18F]FAHA PET clearly showed increased HDAC activity suggestive of cisplatin neurotoxicity in vivo, which was blocked by SAHA pretreatment.

Sensitive detection of malachite green and crystal violet by nonlinear laser wave mixing and capillary electrophoresis.

An ultrasensitive label-free antibody-free detection method for malachite green and crystal violet is presented using nonlinear laser wave-mixing spectroscopy and capillary zone electrophoresis. Wave-mixing spectroscopy provides a sensitive absorption-based detection method for trace analytes. This is accomplished by forming dynamic gratings within a sample cell, which diffracts light to create a coherent laser-like signal beam with high optical efficiency and high signal-to-noise ratio. A cubic dependence on laser power and square dependence on analyte concentration make wave mixing sensitive enough to detect molecules in their native form without the use of fluorescent labels for signal enhancement. A 532 nm laser and a 635 nm laser were used for malachite green and crystal violet sample excitation. The use of two lasers of different wavelengths allows the method to simultaneously detect both analytes. Selectivity is obtained through the capillary zone electrophoresis separation, which results in characteristic migration times. Measurement in capillary zone electrophoresis resulted in a limit of detection of 6.9 × 10(-10)M (2.5 × 10(-19) mol) for crystal violet and 8.3 × 10(-11)M (3.0 × 10(-20) mol) for malachite green at S/N of 2.

Sensitive analysis of α-synuclein by nonlinear laser wave mixing coupled with capillary electrophoresis.

Multi-photon nonlinear laser wave-mixing spectroscopy is a novel absorption-based technique that offers excellent detection sensitivity for biomedical applications, including early diagnosis and investigation of neurodegenerative diseases. α-Synuclein is linked to Parkinson's disease (PD), and characterization of its oligomers and quantification of the protein may contribute to understanding PD. The laser wave-mixing signal has a quadratic dependence on analyte concentration, and hence the technique is effective in monitoring small changes in concentration within biofluids. A wide variety of labels can be employed for laser wave-mixing detection due to its ability to detect both chromophores and fluorophores. In this investigation, two fluorophores and a chromophore are studied and used as labels for the detection of α-synuclein. Wave-mixing detection limits of PD-related protein conjugated with fluorescein isothiocyanate, QSY 35 acetic acid, succinimidyl ester, and Chromeo P503 were determined to be 1.4 × 10(-13) M, 1.4 × 10(-10) M, and 1.9 × 10(-13) M, respectively. Based on the laser probe volume used, the corresponding mass detection limits were determined to be 1.1 × 10(-23) mol, 1.1 × 10(-20) mol, and 1.5 × 10(-23) mol. This study also presents molecular-based separation and quantification of α-synuclein by laser wave mixing coupled with capillary electrophoresis.

Novel Histone Deacetylase Class IIa Selective Substrate Radiotracers for PET Imaging of Epigenetic Regulation in the Brain.

Histone deacetylases (HDAC's) became increasingly important targets for therapy of various diseases, resulting in a pressing need to develop HDAC class- and isoform-selective inhibitors. Class IIa deacetylases possess only minimal deacetylase activity against acetylated histones, but have several other client proteins as substrates through which they participate in epigenetic regulation. Herein, we report the radiosyntheses of the second generation of HDAC class IIa-specific radiotracers: 6-(di-fluoroacetamido)-1-hexanoicanilide (DFAHA) and 6-(tri-fluoroacetamido)-1-hexanoicanilide ([18F]-TFAHA). The selectivity of these radiotracer substrates to HDAC class IIa enzymes was assessed in vitro, in a panel of recombinant HDACs, and in vivo using PET/CT imaging in rats. [18F]TFAHA showed significantly higher selectivity for HDAC class IIa enzymes, as compared to [18F]DFAHA and previously reported [18F]FAHA. PET imaging with [18F]TFAHA can be used to visualize and quantify spatial distribution and magnitude of HDAC class IIa expression-activity in different organs and tissues in vivo. Furthermore, PET imaging with [18F]TFAHA may advance the understanding of HDACs class IIa mediated epigenetic regulation of normal and pathophysiological processes, and facilitate the development of novel HDAC class IIa-specific inhibitors for therapy of different diseases.

20-year experience with intraoperative high-dose-rate brachytherapy for pediatric sarcoma: outcomes, toxicity, and practice recommendations.

PURPOSE: To assess outcomes and toxicity of high-dose-rate intraoperative radiation therapy (HDR-IORT) in the management of pediatric sarcoma. METHODS AND MATERIALS: Seventy-five pediatric patients underwent HDR-IORT for sarcoma from May 1993 to November 2013. The median age was 9 years old (36 patients were ≤ 6 years old). HDR-IORT was part of initial therapy in 37 patients (49%) and for recurrent disease in 38 patients (51%). Forty-one patients (55%) received HDR-IORT and postoperative external beam RT (PORT), and 22 patients (29%) were previously treated with external beam radiation therapy to the IORT site. Local control (LC), overall survival (OS) and event-free survival (EFS) were estimated using Kaplan-Meier methods. RESULTS: At a median follow-up of 7.8 years for surviving patients, 5-year projected rates of LC, EFS, and OS were 63% (95% confidence interval [CI] 50%-76%), 33% (95% CI 21%-45%), and 43% (95% CI 30%-55%), with a median survival of 3.1 years. The 5-year LC, EFS, and OS rates for patients with recurrent disease were 46% (95% CI, 28%-64%), 30% (95% CI, 13%-46%), and 36% (95% CI, 18%-54%). Acute toxicity ≥ grade 3 occurred in 2 (2.5%) treatments; late toxicity ≥ grade 3 occurred in 4 (5.3%) patients 0.3-9.9 years after HDR-IORT. The incidence of toxicity ≥ grade 3 was not associated with HDR-IORT applicator size, HDR-IORT dose, prior RT or PORT, or prior or postoperative chemotherapy, but all toxicity ≥ grade 3 occurred in patients ≤ 6 years treated with HDR-IORT doses ≥ 12 Gy. CONCLUSIONS: HDR-IORT is a well-tolerated component of multimodality therapy for pediatric sarcoma, allowing additional local treatment while reducing external beam exposure. Taking clinical considerations into account, doses between 8-12 Gy are appropriate for HDR-IORT in patients ≤ 6 years of age.

Intraoperative phosphorus-32 brachytherapy plaque for multiply recurrent high-risk epidural neuroblastoma.

Achieving local control is a crucial component in the management of neuroblastoma, but this may be complicated in the setting of prior radiation treatment, especially when the therapeutic target is in proximity to critical structures such as the spinal cord. The authors describe a pediatric patient with multiply recurrent neuroblastoma and prior high-dose radiation therapy to the spine who presented with progressive epidural disease. The patient was managed with resection and intraoperative high-dose-rate brachytherapy using a phosphorus-32 ((32)P) plaque previously developed for the treatment of brain and spine lesions.

Focal low-dose rate brachytherapy for the treatment of prostate cancer.

Whole-gland low-dose rate (LDR) brachytherapy has been a well-established modality of treating low-risk prostate cancer. Treatment in a focal manner has the advantages of reduced toxicity to surrounding organs. Focal treatment using LDR brachytherapy has been relatively unexplored, but it may offer advantages over other modalities that have established experiences with a focal approach. This is particularly true as prostate cancer is being detected at an earlier and more localized stage with the advent of better detection methods and newer imaging modalities.

Imaging epigenetic regulation by histone deacetylases in the brain using PET/MRI with ¹8F-FAHA.

Epigenetic modifications mediated by histone deacetylases (HDACs) play important roles in the mechanisms of different neurologic diseases and HDAC inhibitors (HDACIs) have shown promise in therapy. However, pharmacodynamic profiles of many HDACIs in the brain remain largely unknown due to the lack of validated methods for noninvasive imaging of HDAC expression-activity. In this study, dynamic PET/CT imaging was performed in 4 rhesus macaques using [(18)F]FAHA, a novel HDAC substrate, and [(18)F]fluoroacetate, the major radio-metabolite of [(18)F]FAHA, and fused with corresponding MR images of the brain. Quantification of [(18)F]FAHA accumulation in the brain was performed using a customized dual-tracer pharmacokinetic model. Immunohistochemical analyses of brain tissue revealed the heterogeneity of expression of individual HDACs in different brain structures and cell types and confirmed that PET/CT/MRI with [(18)F]FAHA reflects the level of expression-activity of HDAC class IIa enzymes. Furthermore, PET/CT/MRI with [(18)F]FAHA enabled non-invasive, quantitative assessment of pharmacodynamics of HDAC inhibitor SAHA in the brain.

Pharmacokinetics, metabolism, biodistribution, radiation dosimetry, and toxicology of (18)F-fluoroacetate ((18)F-FACE) in non-human primates.

INTRODUCTION: To facilitate the clinical translation of (18)F-fluoroacetate ((18)F-FACE), the pharmacokinetics, biodistribution, radiolabeled metabolites, radiation dosimetry, and pharmacological safety of diagnostic doses of (18)F-FACE were determined in non-human primates. METHODS: (18)F-FACE was synthesized using a custom-built automated synthesis module. Six rhesus monkeys (three of each sex) were injected intravenously with (18)F-FACE (165.4 ± 28.5 MBq), followed by dynamic positron emission tomography (PET) imaging of the thoracoabdominal area during 0-30 min post-injection and static whole-body PET imaging at 40, 100, and 170 min. Serial blood samples and a urine sample were obtained from each animal to determine the time course of (18)F-FACE and its radiolabeled metabolites. Electrocardiograms and hematology analyses were obtained to evaluate the acute and delayed toxicity of diagnostic dosages of (18)F-FACE. The time-integrated activity coefficients for individual source organs and the whole body after administration of (18)F-FACE were obtained using quantitative analyses of dynamic and static PET images and were extrapolated to humans. RESULTS: The blood clearance of (18)F-FACE exhibited bi-exponential kinetics with half-times of 4 and 250 min for the fast and slow phases, respectively. A rapid accumulation of (18)F-FACE-derived radioactivity was observed in the liver and kidneys, followed by clearance of the radioactivity into the intestine and the urinary bladder. Radio-HPLC analyses of blood and urine samples demonstrated that (18)F-fluoride was the only detectable radiolabeled metabolite at the level of less than 9% of total radioactivity in blood at 180 min after the (18)F-FACE injection. The uptake of free (18)F-fluoride in the bones was insignificant during the course of the imaging studies. No significant changes in ECG, CBC, liver enzymes, or renal function were observed. The estimated effective dose for an adult human is 3.90-7.81 mSv from the administration of 185-370 MBq of (18)F-FACE. CONCLUSIONS: The effective dose and individual organ radiation absorbed doses from administration of a diagnostic dosage of (18)F-FACE are acceptable. From a pharmacologic perspective, diagnostic dosages of (18)F-FACE are non-toxic in primates and, therefore, could be safely administered to human patients for PET imaging.