Rapid analysis for metabolites of 11C-labelled drugs: fate of [11C]-S-4-(tert.-butylamino-2-hydroxypropoxy)-benzimidazol-2-one in the dog.
Positron emission tomography (PET) requires the use of compounds labelled with short-lived, positron-emitting isotopes (e.g., t1/2 of 11C approximately 120 min). As the concentration of unbound, non-metabolised drug is required as the input function for modeling, this presents particular problems for the study of the kinetics and metabolism of such compounds. We have now developed a rapid extraction procedure, followed by high-performance liquid chromatography using a short analytical column coupled to an on-line gamma-detector to determine the metabolism and kinetics of a non-selective beta-adrenergic antagonist of high affinity, S-4-(tert.-butylamino-2-hydroxypropoxy)benzimidazol-2-one. This antagonist is potentially well suited to the non-invasive localisation of beta-receptors in vivo. The ligand was rapidly taken up into the beta-receptor pool or excreted in urine, with less than 5% of the drug converted to metabolites. Plasma protein binding was only 16%. No significant metabolism of the ligand was observed in the anaesthetised dog, and, therefore, no correction for blood metabolite concentration is required for kinetic analysis of the 11C-labelled ligand during PET studies in this species. The analytical method reported here should be widely applicable: quantification of metabolites enables accurate estimation of the input function and is critical to the interpretation of PET data.
Department of Medicine, Royal Postgraduate Medical School, London, UK.
H A
HA
Jones
C G
CG
Rhodes
M P
MP
Law
J M
JM
Becket
J C
JC
Clark
A R
AR
Boobis
G W
GW
Taylor
D000319:Adrenergic beta-Antagonists / Q000097:blood / Q000378:metabolism* / Q000652:urine; D000818:Animals; D001562:Benzimidazoles / Q000097:blood / Q000378:metabolism* / Q000652:urine; D002250:Carbon Radioisotopes; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D004285:Dogs; D005260:Female; D008297:Male; D011412:Propanolamines / Q000097:blood / Q000378:metabolism* / Q000652:urine; D014055:Tomography, Emission-Computed
D000319:Adrenergic beta-Antagonists; D001562:Benzimidazoles; D002250:Carbon Radioisotopes; D011412:Propanolamines; C033394:CGP 12177