[18F]DPA-714: Effect of co-medications, age, sex, BMI and TSPO polymorphism on the human plasma input function.

PURPOSE: We aimed to assess the effect of concomitant medication, age, sex, body mass index and 18-kDa translocator protein (TSPO) binding affinity status on the metabolism and plasma pharmacokinetics of [18F]DPA-714 and their influence on the plasma input function in a large cohort of 201 subjects who underwent brain and whole-body PET imaging to investigate the role of neuroinflammation in neurological diseases. METHODS: The non-metabolized fraction of [18F]DPA-714 was estimated in venous plasma of 138 patients and 63 healthy controls (HCs; including additional arterial sampling in 16 subjects) during the 90 min brain PET acquisition using a direct solid-phase extraction method. The mean fraction between 70 and 90 min post-injection ([18F]DPA-71470-90) and corresponding normalized plasma concentration (SUV70-90) were correlated with all factors using a multiple linear regression model. Differences between groups (arterial vs venous measurements; HCs vs patients; high- (HAB), mixed- (MAB) and low-affinity binders (LAB); subjects with vs without co-medications, females vs males were also assessed using the non-parametric Mann-Whitney or Kruskal-Wallis ANOVA tests. Finally, the impact of co-medications on the brain uptake of [18F]DPA-714 at equilibrium was investigated. RESULTS: As no significant differences were observed between arterial and venous [18F]DPA-71470-90 and SUV70-90, venous plasma was used for correlations. [18F]DPA-71470-90 was not significantly different between patients and HCS (59.7 ± 12.3% vs 60.2 ± 12.9%) despite high interindividual variability. However, 47 subjects exhibiting a huge increase or decrease of [18F]DPA-71470-90 (up to 88% or down to 23%) and SUV70-90 values (2-threefold) were found to receive co-medications identified as inhibitors or inducers of CYP3A4, known to catalyse [18F]DPA-714 metabolism. Comparison between cortex-to-plasma ratios using individual input function (VTIND) or population-based input function derived from untreated HCs (VTPBIF) indicated that non-considering the individual metabolism rate led to a bias of about 30% in VT values. Multiple linear regression model analysis of subjects free of these co-medications suggested significant correlations between [18F]DPA-71470-90 and age, BMI and sex while TSPO polymorphism did not influence the metabolism of the radiotracer. [18F]DPA-714 metabolism fell with age and BMI and was significantly faster in females than in males. Whole-body PET/CT exhibited a high uptake of the tracer in TSPO-rich organs (heart wall, spleen, kidneys…) and those involved in metabolism and excretion pathways (liver, gallbladder) in HAB and MAB with a strong decrease in LAB (-89% and -85%) resulting in tracer accumulation in plasma (4.5 and 3.3-fold increase). CONCLUSION: Any co-medication that inhibits or induces CYP3A4 as well as TSPO genetic status, age, BMI and sex mostly contribute to interindividual variations of the radiotracer metabolism and/or concentration that may affect the input function of [18F]DPA-714 and consequently its human brain and peripheral uptake. TRIAL REGISTRATION: INFLAPARK, NCT02319382, registered December 18, 2014, retrospectively registered; IMABIO 3, NCT01775696, registered January 25, 2013, retrospectively registered; INFLASEP, NCT02305264, registered December 2, 2014, retrospectively registered; EPI-TEP, EudraCT 2017-003381-27, registered September 24, 2018.

[18F]DPA-714 PET imaging of translocator protein TSPO (18 kDa) in the normal and excitotoxically-lesioned nonhuman primate brain.

PURPOSE: We aimed to characterize pharmacologically the TSPO- radioligand [(18)F]DPA-714 in the brain of healthy cynomolgus monkeys and evaluate the cellular origin of its binding in a model of neurodegeneration induced by intrastriatal injection of quinolinic acid (QA). METHODS: [(18)F]DPA-714 PET images were acquired before and at 2, 7, 14, 21, 49, 70, 91 days after putaminal lesioning. Blocking and displacement studies were carried out (PK11195). Different modelling approaches estimated rate constants and V T (total distribution volume) which was used to measure longitudinal changes in the lesioned putamen. Sections for immunohistochemical labelling were prepared at the same time-points to evaluate correlations between in vivo [(18)F]DPA-714 binding and microglial/astrocytic activation. RESULTS: [(18)F]DPA-714 showed a widespread distribution with a higher signal in the thalamus and occipital cortex and lower binding in the cerebellum. TSPO was expressed throughout the whole brain and about 73 % of [(18)F]DPA-714 binding was specific for TSPO in vivo. The one-tissue compartment model (1-TCM) provided good and reproducible estimates of V T and rate constants, and V T values from the 1-TCM and the Logan approach were highly correlated (r (2) = 0.85). QA lesioning induced an increase in V T, which was +17 %, +54 %, +157 % and +39 % higher than baseline on days 7, 14, 21 and 91 after QA injection, respectively. Immunohistochemistry revealed an early microglial and a delayed astrocytic activation after QA injection. [(18)F]DPA-714 binding matched TSPO immunopositive areas and showed a stronger colocalization with CD68 microglia than with GFAP-activated astrocytes. CONCLUSION: [(18)F]DPA-714 binds to TSPO with high specificity in the primate brain under normal conditions and in the QA model. This tracer provides a sensitive tool for assessing neuroinflammation in the human brain.

[Validation of a new methodology for characterizing ultrasound contrast agents (UCA)]. / Validation d'un banc hydrodynamique pour la caractérisation de produits de contraste ultrasonores (PCUS).

PURPOSE: Validation of an experimental ultrasound system on erythrocyte suspensions with variable levels of aggregation and application to the echogenicity quantification of UCA under quasi-physiologic flow conditions. MATERIALS AND METHODS. The system is constituted with a Couette cell with variable applied shear rates, an ultrasound emitter/receiver and a digital scope for radio-frequency signal acquisition. Ultrasound indices (UI) were defined for the two experimental established protocols based on the gold standard laser methodology. Washed red cells with or without variable Dextran 70 kD concentrations were used to simulate a wide particle size range. A preliminary application to UCA was conducted with Levovist for calibration of the system. RESULTS: For each protocol, applied ten times on identical whole blood samples, a student t-test revealed no significant variation for all UI. Results on washed red cells were in good agreement with Rayleigh's theory of ultrasound backscattering. Significant correlations were obtained between laser and UI for washed red cells with different Dextran concentrations. An elevation of 12.13 dB in backscattered intensity was obtained after addition of Levovist. CONCLUSION: The constituted Couette system allowed reproducible and accurate echogenicity quantification of small scatterers such as UCA in quasi-physiologic blood flow conditions.