Standardized uptake values (SUV) of ¹⁸F-fluorodeoxyglucose in six brain regions in house sparrow females with empty implants (n = 5), estradiol implants (E2, n = 10), or empty implants ~1 month after having an estradiol implant (post-E2; n = 5) in response to house sparrow (HOSP) or white-throated sparrow (WTSP) song.

<p>These six regions were included in our analysis because they contain areas previously associated with auditory perception and song recognition. See <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0182875#pone.0182875.t001" target="_blank">Table 1</a> for statistical results from linear mixed models.</p

Positron emission tomography (PET) images of female house sparrow brain uptake of ¹⁸F-fluorodeoxyglucose.

<p>Images were processed as follows: a) Computed tomography (CT) images from a published canary atlas were registered with house sparrow CT images using software registration tools. b) Canary atlas regions of interest were transformed to the co-registered sparrow CT and positron emission tomography (PET) images. c) Sparrow regions of interest were created using regions of interest from the canary atlas.</p

Study design.

<p>Top: In a repeated-measures design, female house sparrows (n = 10) received either an empty or estradiol implant and underwent two imaging sessions. Implants were then removed, and after a month, birds received the other implant type and underwent two more imaging sessions. Bottom: Before each imaging session, a female sparrow was given an intraperitoneal (IP) injection of ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) while awake and then exposed to 20 min of song from either male house sparrows or white-throated sparrows.</p

Effects of hormone treatment, brain region, song type, scan number and hormone treatment x song type interactions on ¹⁸F-fluorodeoxyglucose standardized uptake values (SUV) in female house sparrow brain (<i>Passer domesticus</i>).

<p>Results are from linear mixed models with individual bird as a random effect. To account for differences in plasma glucose concentrations and injection efficiency, we also performed analyses on glucose-normalized and lung-normalized SUV. See text for more details on normalization. Significant model effects are in bold.</p

Quantitative projection of human brain penetration of the H₃ antagonist PF-03654746 by integrating rat-derived brain partitioning and PET receptor occupancy

<p>1. Unbound brain drug concentration (<i>C</i>_b,u), a valid surrogate of interstitial fluid drug concentration (<i>C</i>_ISF), cannot be directly determined in humans, which limits accurately defining the human <i>C</i>_b,u:<i>C</i>_p,u of investigational molecules.</p> <p>2. For the H₃R antagonist (1<i>R</i>,3<i>R</i>)-<i>N</i>-ethyl-3-fluoro-3-[3-fluoro-4-(pyrrolidin-1-lmethyl)phenyl]cyclobutane-1-carboxamide (<b>PF-03654746</b>), we interrogated <i>C</i>_b,u:<i>C</i>_p,u in humans and nonhuman primate (NHP).</p> <p>3. In rat, <b>PF-03654746</b> achieved net blood–brain barrier (BBB) equilibrium (<i>C</i>_b,u:<i>C</i>_p,u of 2.11).</p> <p>4. In NHP and humans, the PET receptor occupancy-based <i>C</i>_p,u IC₅₀ of <b>PF-03654746</b> was 0.99 nM and 0.31 nM, respectively, which were 2.1- and 7.4-fold lower than its <i>in vitro</i> human H₃ <i>K</i>_i (2.3 nM).</p> <p>5. In an attempt to understand this higher-than-expected potency in humans and NHP, rat-derived <i>C</i>_b,u:<i>C</i>_p,u of <b>PF-03654746</b> was integrated with <i>C</i>_p,u IC₅₀ to identify unbound (neuro) potency of <b>PF-03654746</b>, <i>n</i>IC₅₀.</p> <p>6. The <i>n</i>IC₅₀ of <b>PF-03654746</b> was 2.1 nM in NHP and 0.66 nM in human which better correlated (1.1- and 3.49-fold lower) with <i>in vitro</i> human H₃ <i>K</i>_i (2.3 nM).</p> <p>7. This correlation of the <i>n</i>IC₅₀ and <i>in vitro h</i>H₃ <i>K</i>_i suggested the translation of net BBB equilibrium of <b>PF-03654746</b> from rat to NHP and humans, and confirmed the use of <i>C</i>_p,u as a reliable surrogate of <i>C</i>_b,u.</p> <p>8. Thus, <i>n</i>IC₅₀ quantitatively informed the human <i>C</i>_b,u:<i>C</i>_p,u of <b>PF-03654746</b>.</p

Additional file 1 of Drug characteristics derived from kinetic modeling: combined 11C-UCB-J human PET imaging with levetiracetam and brivaracetam occupancy of SV2A

Additional file 1: Fig. S1. 11C-UCB-J activity curves in putamen (closed circles) with model fits (solid curves). a and b Displacement (LEV, 1500 mg at 60 min) and post-dose scans, c and d displacement (BRV, 200 mg at 60 min) and post-dose scans. CND(t) and CS(t) was displayed in the dotted curves and break curves, respectively. Fig. S2. 11C-UCB-J activity curves in cerebellum (closed circles) with model fits (solid curves). a and b displacement (LEV, 1500 mg at 60 min) and post-dose scans, c and d displacement (BRV, 200 mg at 60 min) and post-dose scans. CND(t) and CS(t) was displayed in the dotted curves and break curves, respectively. Fig. S3. Concentrations of AED in the plasma and non-displaceable AED in the putamen (DND(t)) and occupancy curves by LEV (a, b) and BRV (c, d). Insets in (b) and (d) show the occupancy curves for the first 2 h. Fig. S4. Concentrations of AED in the plasma and non-displaceable AED in the cerebellum (DND(t)) and occupancy curves by LEV (a, b) and BRV (c, d). Insets in (b) and (d) show the occupancy curves for the first 2 h. Table S1. Kinetic parameters estimated using the one-tissue compartment model (LEV: n = 4, BRV: n = 5)

Increased Nanoparticle Delivery to Brain Tumors by Autocatalytic Priming for Improved Treatment and Imaging

The blood–brain barrier (BBB) is partially disrupted in brain tumors. Despite the gaps in the BBB, there is an inadequate amount of pharmacological agents delivered into the brain. Thus, the low delivery efficiency renders many of these agents ineffective in treating brain cancer. In this report, we proposed an “autocatalytic” approach for increasing the transport of nanoparticles into the brain. In this strategy, a small number of nanoparticles enter into the brain <i>via</i> transcytosis or through the BBB gaps. After penetrating the BBB, the nanoparticles release BBB modulators, which enables more nanoparticles to be transported, creating a positive feedback loop for increased delivery. Specifically, we demonstrated that these autocatalytic brain tumor-targeting poly­(amine-<i>co</i>-ester) terpolymer nanoparticles (ABTT NPs) can readily cross the BBB and preferentially accumulate in brain tumors at a concentration of 4.3- and 94.0-fold greater than that in the liver and in brain regions without tumors, respectively. We further demonstrated that ABTT NPs were capable of mediating brain cancer gene therapy and chemotherapy. Our results suggest ABTT NPs can prime the brain to increase the systemic delivery of therapeutics for treating brain malignancies