Beta-adrenergic receptor imaging with positron emission tomography

In vivo quantification of β-adrenoceptors in the brain, heart and lung could be very valuable for the investigation of these receptors in neuropathologies, myocardial and pulmonary diseases, and for monitoring the effects of treatment. The aim of this thesis was the development of a method to image β-adrenoceptors in the human brain and heart with PET and the validation of a tracer kinetic model to in vivo quantify receptor densities.... Zie: Summary

PET imaging of beta-adrenoceptors in human brain: A realistic goal or a mirage?

Beta-adrenoceptors are predominantly located in the cerebral cortex, nucleus accumbens and striatum. At lower densities, they are also present in amygdala, hippocampus and cerebellum. Beta-2 sites regulate glial proliferation during ontogenic development, after trauma and in neurodegenerative diseases. The densities of beta-1 adrenoceptors are changed by stress, in several mood disorders (depression, excessive hostility, schizophrenia) and during treatment of patients with antidepressants. A technique for beta-adrenoceptor imaging in the human brain is not yet available. Although 24 (ant)agonists have been labeled with either 11C or 18F and some of these are successful myocardial imaging agents, only two (S-1’-18F-fluorocarazolol and S-1’-18F-fluoroethylcarazolol) could actually visualize ß-adrenoceptors within the central nervous system. Unfortunately, these radiopharmaceuticals showed a positive Ames test. They may be mutagenic and cannot be employed for human studies. Screening of more than 150 beta-blockers described in the literature yields only two compounds (exaprolol and L643,717) which can still be radiolabeled and evaluated for ß-adenoceptor imaging. However, other imaging techniques could be examined. Cerebral ß-adrenoceptors might be labeled after temporary opening of the blood-brain barrier (BBB) and simultaneous administration of a hydrophilic ligand such as S-11C-CGP12388. Another approach to target ß-adrenoceptor ligands to the CNS is esterification of a myocardial imaging agent (such as 11C-CGP12177), resulting in a lipophilic prodrug which can cross the BBB and is split by tissue esterases. BBB opening is not feasible in healthy subjects, but the prodrug approach may be successful and deserves to be explored

Validation of S-1 '-[F-18]fluorocarazolol for in vivo imaging and quantification of cerebral beta-adrenoceptors

S-1'-[F-18]fluorocarazolol (S-(-)-4-(2-hydroxy-3-(1'-[F-18]fluoroisopropyl)-aminopropoxy)carbazole, a non-subtype-selective beta-adrenoceptor antagonist) has been investigated for in vivo studies of beta-adrenoceptors. Previous results indicated that uptake of this radioligand in heart and lung can be inhibited by beta-adrenoceptor agonists and antagonists. In the present study, blocking, displacement and saturation experiments were performed in rats, in combination with metabolite analysis to investigate the suitability of this radioligand for in vivo positron emission tomography (PET) imaging and quantification of beta-adrenoceptors in the brain. The results demonstrate that, (i) the uptake of S-1'-[F-18]fluorocarazolol reflects specific binding to beta-adrenoceptors, (ii) binding of S-1'-[F-18]fluorocarazolol to atypical or non-beta-adrenergic sites is negligible, (iii) uptake of radioactive metabolites in the brain is less than 25% of total radioactivity, 60 min after injection, (iv) in vivo measurements of receptor densities (B-max) in cortex, cerebellum, heart, lung and erythrocytes are within range of densities determined from in vitro assays, (v) binding of S-1'-[F-18]fluorocarazolol can be displaced. In conclusion, S-1'-[F-18]fluorocarazolol seems to possess the appropriate characteristics to visualize and quantify beta-adrenoceptors in vivo in the central nervous system using PET. (C) 1998 Elsevier Science B.V. All rights reserved

Positron emission tomography studies of human airways using an inhaled beta-adrenoceptor antagonist, S-11C-CGP 12388

Objectives: Positron emission tomography (PET) scanning may provide information on changes in the density and affinity of airway beta-adrenoceptors in lung diseases. However, the injection of a radiolabeled P-blocker results in a pulmonary PET signal that reflects the binding of the ligand in the alveoli and not in the airways. Better discrimination between alveolar and airway beta-adrenoceptors may be possible with an inhaled radioligand. Design: A nebulizer was used to administer the antagonist S-C-11-CGP12388 in aerosol form. Eight volunteers inhaled the tracer twice, at baseline and after pretreatment with a beta-adrenergic drug. In both PET scan studies, a dynamic scan of the lungs was followed by a whole-body scan to assess the inhaled dose. Pulmonary uptake was quantified using a region-of-interest-based analysis. Setting: University hospital. Participants: Healthy volunteers. Interventions: Pretreatment consisted either of inhaled salbutamol (400 mu g, 20 min before the scan), or orally administered pindolol (3 X 5 mg during a period of 16 h before PET scanning). Results: Drug pretreatment did not affect pulmonary deposition of the radioligand. The agonist salbutamol accelerated the monoexponential washout of C-11 not only in the peripheral lung (mainly alveoli), but also in the central lung (mainly airways) and in the main bronchi. An even larger increase of the washout rate was induced by the antagonist pindolol. Conclusion: The similar effects of pindolol and salbutamol on tracer kinetics suggest that accelerated washout is due to the blockade of beta-adrenoceptors. Thus, the interaction of drugs with airway beta-adrenoceptors can be visualized using PET scanning and an inhaled radioligand