The Distribution and Kinetics of [18F]6-Fluoro-3-O-Methyl-l-Dopa in the Human Brain

1994 ◽  
Vol 14 (4) ◽  
pp. 664-670 ◽  
Author(s):  
Lindi Wahl ◽  
Raman Chirakal ◽  
Gunter Firnau ◽  
E. Stephen Garnett ◽  
Claude Nahmias
Keyword(s):  
Blood Brain Barrier ◽  
Time Course ◽  
Nonhuman Primates ◽  
Dopamine Metabolism ◽  
Brain Barrier ◽  
Blood Brain ◽  
Measured Time ◽  
Bidirectional Transport ◽  
Kinetics Of ◽  
The Brain

The analysis of positron tomographic studies of 3,4-dihydroxyphenylethylamine (dopamine) metabolism in which [18F]6-fluoro-l-3,4-dihydroxyphenylalanine (F-dopa) is used as a tracer is confounded by the presence of [18F]6-fluoro-3- O-methyl-l-3,4-dihydroxyphenylalanine (OMFD). This labeled molecule, formed by the action of peripheral cathechol- O-methyltransferase on F-dopa, crosses the blood–brain barrier and contributes to the radioactivity measured by the tomograph. Corrections for this radioactivity in the brain have been proposed. They rely upon the assumption that regional variations in the handling of this molecule by the brain are negligible. Although this assumption is pivotal for the proper quantification of dopamine metabolism using F-dopa, the distribution and kinetics of OMFD have never been studied in humans. We present results in humans that show that there is little selective regional 18F accumulation in the brain, that the distribution volume of OMFD is close to unity, and that a single, reversible compartment is adequate to model the measured time course of radioactivity after an OMFD injection. Analysis of plasma samples for labeled metabolites showed that more than 95% of the radioactivity was associated with OMFD at all times. Our results for OMFD kinetics are in accord with published results obtained in nonhuman primates and for the bidirectional transport of large neutral amino acids across the blood-brain barrier measured using a synthetic amino acid. However, our results also indicate that there are small but significant differences in OMFD kinetics in different parts of the brain that may prevent inferences about the handling of OMFD in one part of the brain from being extended to other parts of the brain.

scholarly journals Distribution and Kinetics of 3-O-Methyl-6-[18F]fluoro-L-DOPA in the Rhesus Monkey Brain

1991 ◽  
Vol 11 (5) ◽  
pp. 726-734 ◽  
Author(s):  
Doris J. Doudet ◽  
Catherine A. McLellan ◽  
Richard Carson ◽  
H. Richard Adams ◽  
Hitoshi Miyake ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Rhesus Monkeys ◽  
Brain Barrier ◽  
Nigrostriatal System ◽  
Dopamine System ◽  
Blood Brain ◽  
Homogenous Distribution ◽  
Plasma Metabolite ◽  
Kinetics Of ◽  
The Brain

Most attempts to model accurately [18F]-DOPA imaging of the dopamine system are based on the assumptions that its main peripheral metabolite, 3-O-methyl-6-[18F]fluoro-L-DOPA ([18F]3-OM-DOPA), crosses the blood-brain barrier but is present as a homogenous distribution throughout the brain, in part because it is not converted into [18F]DOPA in significant quantities. These assumptions were based mainly on data in rodents. Little information is available in the primate. To verify the accuracy of the above assumptions, we administered 18F-labeled 3-OM-DOPA to normal rhesus monkeys and animals with lesions of the DA nigrostriatal system. No selective 18F regional accumulation in brain was apparent in normal or lesioned animals. The plasma metabolite analysis revealed that only the negatively charged metabolites (e.g., sulfated conjugates) that do not cross the blood-brain barrier were found in significant quantities in the plasma. A one-compartment, three-parameter model was adequate to describe the kinetics of [18F]3-OM-DOPA. In conclusion, assumptions concerning [18F]3-OM-DOPA's behavior in brain appear acceptable for [18F]DOPA modeling purposes.

Effects of insulin on hexose transport across blood-brain barrier in normoglycemia

1987 ◽  
Vol 252 (3) ◽  
pp. E299-E303 ◽  
Author(s):  
H. Namba ◽  
G. Lucignani ◽  
A. Nehlig ◽  
C. Patlak ◽  
K. Pettigrew ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Rate Constants ◽  
Time Course ◽  
Brain Barrier ◽  
Tissue Concentrations ◽  
Arterial Blood ◽  
Blood Brain ◽  
Measured Time ◽  
Time Courses ◽  
Arterial Plasma

The effects of insulin on 3-O-[14C]methylglucose transport across the blood-brain barrier (BBB) were studied in conscious rats under steady-state normoglycemic conditions. The [14C]methylglucose was infused intravenously at a constant rate, and animals were killed at various times between 5 and 30 min after the initiation of the infusion. The time course of the arterial plasma concentration of [14C]methylglucose was determined in timed arterial blood samples taken during the infusion. Local cerebral tissue concentrations of [14C]methylglucose at the time of killing were determined by quantitative autoradiography of brain sections. The rate constants for inward and outward transport of [14C]methylglucose across the BBB, K1, and k2, respectively, were estimated by a least-squares, best-fit of a kinetic equation to the measured time courses of plasma and tissue concentrations. K1 and k2 were reduced by an average of 24 and 31%, respectively, in gray matter and 7 and 16% in white matter from values estimated similarly in normal insulinemic control rats. The equilibrium distribution ratio, K1/k2, for [14C]methylglucose in brain increased by approximately 10–11% in the hyperinsulinemic animals. Because 3-O-[14C]methylglucose shares the same carrier that transports glucose and other hexoses across the BBB, these results suggest that hyperinsulinemia decreases the rate constants for transport but increases the distribution space for hexoses in brain. These effects are, however, quite small and are probably minor or negligible when compared with the major effects of insulin in other tissues.

scholarly journals Impact of blood-brain barrier permeabilization induced by ultrasound associated to microbubbles on the brain delivery and kinetics of cetuximab: An immunoPET study using 89Zr-cetuximab

2020 ◽  
Vol 328 ◽  
pp. 304-312 ◽  
Author(s):  
Vu Long Tran ◽  
Anthony Novell ◽  
Nicolas Tournier ◽  
Matthieu Gerstenmayer ◽  
Arnaud Schweitzer-Chaput ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Brain Delivery ◽  
Blood Brain ◽  
Kinetics Of ◽  
The Brain

scholarly journals Syntheses and in vitro biological evaluation of S1PR1 ligands and PET studies of four F-18 labeled radiotracers in the brain of nonhuman primates

2018 ◽  
Vol 16 (47) ◽  
pp. 9171-9184 ◽  
Author(s):  
Zonghua Luo ◽  
Junbin Han ◽  
Hui Liu ◽  
Adam J. Rosenberg ◽  
Delphine L. Chen ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Nonhuman Primates ◽  
Biological Evaluation ◽  
Brain Barrier ◽  
Blood Brain ◽  
The Brain

Four potent and selective F-18 labeled S1PR1 radiotracers were radiosynthesized and three of them were able to cross blood–brain-barrier and enter into the brain of nonhuman primates.

scholarly journals Kinetics of Blood–Brain Barrier Transport of Monoclonal Antibodies Targeting the Insulin Receptor and the Transferrin Receptor

2021 ◽  
Vol 15 (1) ◽  
pp. 3
Author(s):  
William M. Pardridge
Keyword(s):  
Fusion Protein ◽  
Mathematical Models ◽  
Insulin Receptor ◽  
Blood Brain Barrier ◽  
Transferrin Receptor ◽  
Brain Barrier ◽  
Luminal Membrane ◽  
Blood Brain ◽  
Kinetics Of ◽  
The Brain

Biologic drugs are large molecule pharmaceuticals that do not cross the blood–brain barrier (BBB), which is formed by the brain capillary endothelium. Biologics can be re-engineered for BBB transport as IgG fusion proteins, where the IgG domain is a monoclonal antibody (MAb) that targets an endogenous BBB transporter, such as the insulin receptor (IR) or transferrin receptor (TfR). The IR and TfR at the BBB transport the receptor-specific MAb in parallel with the transport of the endogenous ligand, insulin or transferrin. The kinetics of BBB transport of insulin or transferrin, or an IRMAb or TfRMAb, can be quantified with separate mathematical models. Mathematical models to estimate the half-time of receptor endocytosis, MAb or ligand exocytosis into brain extracellular space, or receptor recycling back to the endothelial luminal membrane were fit to the brain uptake of a TfRMAb or a IRMAb fusion protein in the Rhesus monkey. Model fits to the data also allow for estimates of the rates of association of the MAb in plasma with the IR or TfR that is embedded within the endothelial luminal membrane in vivo. The parameters generated from the model fits can be used to estimate the brain concentration profile of the MAb over time, and this brain exposure is shown to be a function of the rate of clearance of the antibody fusion protein from the plasma compartment.

Ligand and Structure-based Modeling of Passive Diffusion through the Blood-Brain Barrier

2018 ◽  
Vol 25 (9) ◽  
pp. 1073-1089 ◽  
Author(s):  
Santiago Vilar ◽  
Eduardo Sobarzo-Sanchez ◽  
Lourdes Santana ◽  
Eugenio Uriarte
Keyword(s):  
Blood Brain Barrier ◽  
In Silico ◽  
Passive Diffusion ◽  
Brain Barrier ◽  
Barrier Permeability ◽  
Blood Brain Barrier Permeability ◽  
Blood Brain ◽  
Brain Barrier Permeability ◽  
Different Types ◽  
The Brain

Background: Blood-brain barrier transport is an important process to be considered in drug candidates. The blood-brain barrier protects the brain from toxicological agents and, therefore, also establishes a restrictive mechanism for the delivery of drugs into the brain. Although there are different and complex mechanisms implicated in drug transport, in this review we focused on the prediction of passive diffusion through the blood-brain barrier. Methods: We elaborated on ligand-based and structure-based models that have been described to predict the blood-brain barrier permeability. Results: Multiple 2D and 3D QSPR/QSAR models and integrative approaches have been published to establish quantitative and qualitative relationships with the blood-brain barrier permeability. We explained different types of descriptors that correlate with passive diffusion along with data analysis methods. Moreover, we discussed the applicability of other types of molecular structure-based simulations, such as molecular dynamics, and their implications in the prediction of passive diffusion. Challenges and limitations of experimental measurements of permeability and in silico predictive methods were also described. Conclusion: Improvements in the prediction of blood-brain barrier permeability from different types of in silico models are crucial to optimize the process of Central Nervous System drug discovery and development.

Liposomes: Novel Drug Delivery Approach for Targeting Parkinson’s Disease

2020 ◽  
Vol 26 (37) ◽  
pp. 4721-4737 ◽  
Author(s):  
Bhumika Kumar ◽  
Mukesh Pandey ◽  
Faheem H. Pottoo ◽  
Faizana Fayaz ◽  
Anjali Sharma ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Drug Delivery ◽  
Parkinson's Disease ◽  
Side Effects ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Brain Targeting ◽  
Neural Cells ◽  
Blood Brain ◽  
The Brain

Parkinson’s disease is one of the most severe progressive neurodegenerative disorders, having a mortifying effect on the health of millions of people around the globe. The neural cells producing dopamine in the substantia nigra of the brain die out. This leads to symptoms like hypokinesia, rigidity, bradykinesia, and rest tremor. Parkinsonism cannot be cured, but the symptoms can be reduced with the intervention of medicinal drugs, surgical treatments, and physical therapies. Delivering drugs to the brain for treating Parkinson’s disease is very challenging. The blood-brain barrier acts as a highly selective semi-permeable barrier, which refrains the drug from reaching the brain. Conventional drug delivery systems used for Parkinson’s disease do not readily cross the blood barrier and further lead to several side-effects. Recent advancements in drug delivery technologies have facilitated drug delivery to the brain without flooding the bloodstream and by directly targeting the neurons. In the era of Nanotherapeutics, liposomes are an efficient drug delivery option for brain targeting. Liposomes facilitate the passage of drugs across the blood-brain barrier, enhances the efficacy of the drugs, and minimize the side effects related to it. The review aims at providing a broad updated view of the liposomes, which can be used for targeting Parkinson’s disease.

Brain Drug Delivery: Overcoming the Blood-brain Barrier to Treat Tauopathies

2020 ◽  
Vol 26 (13) ◽  
pp. 1448-1465 ◽  
Author(s):  
Jozef Hanes ◽  
Eva Dobakova ◽  
Petra Majerova
Keyword(s):  
Drug Delivery ◽  
Blood Brain Barrier ◽  
Neurodegenerative Disorders ◽  
Brain Barrier ◽  
Neuronal Function ◽  
Brain Drug Delivery ◽  
Naturally Occurring ◽  
Blood Brain ◽  
Traditional Approaches ◽  
The Brain

Tauopathies are neurodegenerative disorders characterized by the deposition of abnormal tau protein in the brain. The application of potentially effective therapeutics for their successful treatment is hampered by the presence of a naturally occurring brain protection layer called the blood-brain barrier (BBB). BBB represents one of the biggest challenges in the development of therapeutics for central nervous system (CNS) disorders, where sufficient BBB penetration is inevitable. BBB is a heavily restricting barrier regulating the movement of molecules, ions, and cells between the blood and the CNS to secure proper neuronal function and protect the CNS from dangerous substances and processes. Yet, these natural functions possessed by BBB represent a great hurdle for brain drug delivery. This review is concentrated on summarizing the available methods and approaches for effective therapeutics’ delivery through the BBB to treat neurodegenerative disorders with a focus on tauopathies. It describes the traditional approaches but also new nanotechnology strategies emerging with advanced medical techniques. Their limitations and benefits are discussed.

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