Biomedical subjects

Aren van Waarde

Publications and source records attributed to Aren van Waarde.

21 records · Page 2Linked to original sources

PubMed2002

Measuring drug-related receptor occupancy with positron emission tomography.

Several techniques can be used to measure indirectly the effect of drugs (e.g., EEG, fMRI) in healthy volunteers and in patients. Although each technique has its merits, a direct link between drug efficacy and site of action in vivo usually cannot be established. In addition, when the specific mode of action of a drug has been determined from preclinical studies, it is often not known whether the administered dose is optimal for humans. Both industry and academia are becoming more and more interested in determining the dose-related occupancy of specific targets caused by administration of drugs under test. Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) are noninvasive imaging techniques that can give insight into the relationship between target occupancy and drug efficacy, provided a suitable radioligand is available. Although SPECT has certain advantages (e.g., a long half-life of the radionuclides), the spatial and temporal resolution as well as the labeling possibilities of this technique are limited. This review focuses on PET methodology for conducting drug occupancy studies in humans.

Animals↗

PubMed1998

Visualization of beta-Adrenoceptors Using PET.

PET-investigations of beta-adrenoceptors in heart, lungs, and brain are of great clinical interest. Receptor densities are altered under various pathophysiological conditions. This review gives an overview of PET-research of beta-adrenoceptors. The clinical relevance of in vivo PET-investigations of beta-adrenoceptors is described for heart, lungs, and brain. Results obtained with the available PET-ligands are discussed. [(11)C]CGP 12177 has been successfully applied in patients with cardiac and pulmonary diseases. The complicated labelling procedure prevents widespread use of the radiopharmaceutical. Due to its lipophilicity, [(18)F]-fluorocarazolol is a suitable ligand for cardiac and pulmonary as well as for cerebral sites. Non-specific binding is higher as compared to [(11)C]CGP 12177. Unfavorable toxicity data prevents human use of this ligand. [(11)C]Carazolol shows comparable distribution in heart and lung as [(18)F]fluorocarazolol, but it hardly enters the brain. [(11)C]CGP 12388 displays comparable pharmacokinetics in rats and is much easier prepared than [(11)C]CGP 12177. Therefore [(11)C]CGP 12388 seems a promising PET-ligand for clinical studies of cardiac and pulmonary beta-adrenoceptors. Pilot studies with the long-acting agonist [(11)C]formoterol have indicated that it may be possible to investigate the high affinity state of the beta(2)-subtype.

Journal Article↗

PubMedDate not supplied

Positron emission tomography studies on binding of central nervous system drugs and P-glycoprotein function in the rodent brain.

The permeability of the blood-brain barrier (BBB) is one of the factors determining the bioavailability of drugs in the brain. The BBB only allows passage of lipophilic drugs by passive diffusion. However, some lipophilic drugs hardly enter the brain. The transmembrane protein P-glycoprotein (P-gp) is one of the carrier systems that is responsible for transportation of drugs out of the brain. P-Glycoprotein affects the pharmacokinetics of many drugs and can be inhibited by administration of modulators or competitive substrates. Identification and classification of central nervous system (CNS) drugs as P-gp substrates or inhibitors are of crucial importance in drug development. Positron emission tomography (PET) studies can play an important role in the screening process as a follow-up of high-throughput in vitro assays. Several rodent studies have shown the potential value of PET to measure the effect of P-gp on the pharmacokinetics and brain uptake of radiolabeled compounds. P-Glycoprotein-mediated effects were observed for two 5-HT(1a) receptor ligands, [(18)F]MPPF vs. [carbonyl-(11)C]WAY100635. Under control conditions, the specific brain uptake of [(18)F]MPPF is five- to eightfold lower than that of [(11)C]WAY100635. After cyclosporin A (CsA) modulation, [(18)F]MPPF uptake in the rat brain increased five- to tenfold. Cerebral uptake of [carbonyl-(11)C]WAY100635 was also increased by modulation, but in general the increase was lower than that observed for [(18)F]MPPF (two- to threefold). Brain uptake of the beta-adrenergic receptor ligands [(11)C]carazolol and [(18)F]fluorocarazolol was increased in P-gp knockout mice and CsA-treated rats. Both the specific and nonspecific binding of [(18)F]fluorocarazolol were doubled by CsA. Cerebral uptake of [(11)C]carazolol in rats was much lower than that of [(18)F]fluorocarazolol and no specific binding was measured. After CsA modulation, the uptake of [(11)C]carazolol increased five- to sixfold, but this uptake was not receptor-mediated. Quantitative PET studies in rodents on P-gp functionality demonstrated a dose-dependent increase of radioligands after administration of CsA. Studies with [(11)C]verapamil and [(11)C]carvedilol showed that complete modulation was achieved at 50 mg/kg CsA. The distribution volume of [(11)C]carvedilol increased from 0.25 in the control study to 1.0 after full modulation with CsA. By quantitative PET measurement of P-gp function, the dose of modulators required to increase the concentration of CNS drugs may be determined, which may result in improved drug therapy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗