Focused ultrasound for opening blood-brain barrier and drug delivery monitored with positron emission tomography

Focused ultrasound (FUS) is a minimally-invasive technology used for treatment of many diseases, including diseases related to the colon, uterus, prostate, and brain. Although it has been mainly used for ablative procedures, the ability of FUS to open the blood-brain barrier (BBB) presents a promising new application. However, the mechanism of BBB opening by FUS remains unclear. This review focuses on the use of FUS to open the BBB for enhancing drug delivery and investigating how Positron Emission Tomography (PET) provides insight into the underlying mechanism

Effects of proton therapy on regional [¹⁸F]FDG uptake in non-tumor brain regions of patients treated for head and neck cancer

Background and purpose: Previous pre-clinical research using [18F]FDG-PET has shown that whole-brain photon-based radiotherapy can affect brain glucose metabolism. This study, aimed to investigate how these findings translate into regional changes in brain [18F]FDG uptake in patients with head and neck cancer treated with intensity-modulated proton therapy (IMPT). Materials and methods: Twenty-three head and neck cancer patients treated with IMPT and available [18F]FDG scans before and at 3 months follow-up were retrospectively evaluated. Regional assessment of the [18F]FDG standardized uptake value (SUV) parameters and radiation dose in the left (L) and right (R) hippocampi, L and R occipital lobes, cerebellum, temporal lobe, L and R parietal lobes and frontal lobe were evaluated to understand the relationship between regional changes in SUV metrics and radiation dose. Results: Three months after IMPT, [18F]FDG brain uptake calculated using SUVmean and SUVmax, was significantly higher than that before IMPT. The absolute SUVmean after IMPT was significantly higher than before IMPT in seven regions of the brain (p ≤ 0.01), except for the R (p = 0.11) and L (p = 0.15) hippocampi. Absolute and relative changes were variably correlated with the regional maximum and mean doses received in most of the brain regions. Conclusion: Our findings suggest that 3 months after completion of IMPT for head and neck cancer, significant increases in the uptake of [18F]FDG (reflected by SUVmean and SUVmax) can be detected in several individual key brain regions, and when evaluated jointly, it shows a negative correlation with the mean dose. Future studies are needed to assess whether and how these results could be used for the early identification of patients at risk for adverse cognitive effects of radiation doses in non-tumor tissues.</p

Pharmacokinetic Modeling of [ 18 F]MC225 for Quantification of the P-Glycoprotein Function at the Blood-Brain Barrier in Non-Human Primates with PET

[18F]MC225 has been developed as a weak substrate of P-glycoprotein (P-gp) aimed to measure changes in the P-gp function at the blood–brain barrier with positron emission tomography. This study evaluates [18F]MC225 kinetics in non-human primates and investigates the effect of both scan duration and P-gp inhibition. Three rhesus monkeys underwent two 91-min dynamic scans with blood sampling at baseline and after P-gp inhibition (8 mg/kg tariquidar). Data were analyzed using the 1-tissue compartment model (1-TCM) and 2-tissue compartment model (2-TCM) fits using metabolite-corrected plasma as the input function and for various scan durations (10, 20, 30, 60, and 91 min). The preferred model was chosen according to the Akaike information criterion and the standard errors (%) of the estimated parameters. For the 91-min scan duration, the influx constant K1 increased by 40.7% and the volume of distribution (VT) by 30.4% after P-gp inhibition, while the efflux constant k2 did not change significantly. Similar changes were found for all evaluated scan durations. K1 did not depend on scan duration (10 min—K1 = 0.2191 vs 91 min—K1 = 0.2258), while VT and k2 did. A scan duration of 10 min seems sufficient to properly evaluate the P-gp function using K1 obtained with 1-TCM. For the 91-min scan, VT and K1 can be estimated with a 2-TCM, and both parameters can be used to assess P-gp function

Quantification of P-glycoprotein function at the human blood-brain barrier using [ 18F]MC225 and PET.

INTRODUCTION: P-glycoprotein (P-gp) is one of the most studied efflux transporters at the blood-brain barrier. It plays an important role in brain homeostasis by protecting the brain from a variety of endogenous and exogeneous substances. Changes in P-gp function are associated both with the onset of neuropsychiatric diseases, including Alzheimer's disease and Parkinson's disease, and with drug-resistance, for example in treatment-resistant depression. The most widely used approach to measure P-gp function in vivo is (R)-[ 11C]verapamil PET. (R)-[ 11C]verapamil is, however, an avid P-gp substrate, which complicates the use of this tracer to measure an increase in P-gp function as its baseline uptake is already very low. [ 18F]MC225 was developed to measure both increases and decreases in P-gp function. AIM: The aim of this study was (1) to identify the pharmacokinetic model that best describes [ 18F]MC225 kinetics in the human brain and (2) to determine test-retest variability. METHODS: Five (2 male, 3 female) of fourteen healthy subjects (8 male, 6 female, age 67 ± 5 years) were scanned twice (injected dose 201 ± 47 MBq) with a minimum interval of 2 weeks between scans. Each scanning session consisted of a 60-min dynamic [ 18F]MC225 scan with continuous arterial sampling. Whole brain grey matter data were fitted to a single tissue compartment model, and to reversible and irreversible two tissue-compartment models to obtain various outcome parameters (in particular the volume of distribution (V T), K i, and the rate constants K 1 and k 2). In addition, a reversible two-tissue compartment model with fixed k 3/k 4 was included. The preferred model was selected based on the weighted Akaike Information Criterion (AIC) score. Test-retest variability (TRTV) was determined to assess reproducibility. RESULTS: Sixty minutes post-injection, the parent fraction was 63.8 ± 4.0%. The reversible two tissue compartment model corrected for plasma metabolites with an estimated blood volume (V B) showed the highest AIC weight score of 34.3 ± 17.6%. The TRVT of the V T for [ 18F]MC225 PET scans was 28.3 ± 20.4% for the whole brain grey matter region using this preferred model. CONCLUSION: [ 18F]MC225 V T, derived using a reversible two-tissue compartment model, is the preferred parameter to describe P-gp function in the human BBB. This outcome parameter has an average test-retest variability of 28%. TRIAL REGISTRATION: EudraCT 2020-001564-28 . Registered 25 May 2020.</p

Quantification of P-glycoprotein function at the human blood-brain barrier using [ 18F]MC225 and PET.

INTRODUCTION: P-glycoprotein (P-gp) is one of the most studied efflux transporters at the blood-brain barrier. It plays an important role in brain homeostasis by protecting the brain from a variety of endogenous and exogeneous substances. Changes in P-gp function are associated both with the onset of neuropsychiatric diseases, including Alzheimer's disease and Parkinson's disease, and with drug-resistance, for example in treatment-resistant depression. The most widely used approach to measure P-gp function in vivo is (R)-[ 11C]verapamil PET. (R)-[ 11C]verapamil is, however, an avid P-gp substrate, which complicates the use of this tracer to measure an increase in P-gp function as its baseline uptake is already very low. [ 18F]MC225 was developed to measure both increases and decreases in P-gp function. AIM: The aim of this study was (1) to identify the pharmacokinetic model that best describes [ 18F]MC225 kinetics in the human brain and (2) to determine test-retest variability. METHODS: Five (2 male, 3 female) of fourteen healthy subjects (8 male, 6 female, age 67 ± 5 years) were scanned twice (injected dose 201 ± 47 MBq) with a minimum interval of 2 weeks between scans. Each scanning session consisted of a 60-min dynamic [ 18F]MC225 scan with continuous arterial sampling. Whole brain grey matter data were fitted to a single tissue compartment model, and to reversible and irreversible two tissue-compartment models to obtain various outcome parameters (in particular the volume of distribution (V T), K i, and the rate constants K 1 and k 2). In addition, a reversible two-tissue compartment model with fixed k 3/k 4 was included. The preferred model was selected based on the weighted Akaike Information Criterion (AIC) score. Test-retest variability (TRTV) was determined to assess reproducibility. RESULTS: Sixty minutes post-injection, the parent fraction was 63.8 ± 4.0%. The reversible two tissue compartment model corrected for plasma metabolites with an estimated blood volume (V B) showed the highest AIC weight score of 34.3 ± 17.6%. The TRVT of the V T for [ 18F]MC225 PET scans was 28.3 ± 20.4% for the whole brain grey matter region using this preferred model. CONCLUSION: [ 18F]MC225 V T, derived using a reversible two-tissue compartment model, is the preferred parameter to describe P-gp function in the human BBB. This outcome parameter has an average test-retest variability of 28%. TRIAL REGISTRATION: EudraCT 2020-001564-28 . Registered 25 May 2020.</p

Evaluation of P-glycoprotein function at the blood-brain barrier using [F-18]MC225-PET

P-glycoprotein (P-gp) is an ATP-dependent efflux transporter located at the blood–brain barrier (BBB), involved in the transport of a variety of neurotoxic substances out of the brain. Alterations in P-gp function play an essential role in the pathophysiological mechanisms underlying neurodegenerative disorders