Kinetic analysis of transport and opioid receptor binding of ( sup 3 H)(-)-cyclofoxy in rat brain in vivo: Implications for human studies

Journal Article · Thu Feb 28 23:00:00 EST 1991 · Journal of Cerebral Blood Flow and Metabolism; (USA)

DOI:https://doi.org/10.1038/jcbfm.1991.51· OSTI ID:5961802

Sawada, Y; Kawai, R; McManaway, M; Otsuki, H; Rice, K C; Patlak, C S; Blasberg, R G ^[1]

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1. National Institutes of Health, Bethesda, MD (USA)

(3H)Cyclofoxy (CF: 17-cyclopropylmethyl-3,14-dihydroxy-4,5-alpha-epoxy-6-beta-fluoromorp hinan) is an opioid antagonist with affinity to both mu and kappa subtypes that was synthesized for quantitative evaluation of opioid receptor binding in vivo. Two sets of experiments in rats were analyzed. The first involved determining the metabolite-corrected blood concentration and tissue distribution of CF in brain 1 to 60 min after i.v. bolus injection. The second involved measuring brain washout for 15 to 120 s following intracarotid artery injection of CF. A physiologically based model and a classical compartmental pharmacokinetic model were compared. The models included different assumptions for transport across the blood-brain barrier (BBB); estimates of nonspecific tissue binding and specific binding to a single opiate receptor site were found to be essentially the same with both models. The nonspecific binding equilibrium constant varied modestly in different brain structures (Keq = 3-9), whereas the binding potential (BP) varied over a much broader range (BP = 0.6-32). In vivo estimates of the opioid receptor dissociation constant were similar for different brain structures (KD = 2.1-5.2 nM), whereas the apparent receptor density (Bmax) varied between 1 (cerebellum) and 78 (thalamus) pmol/g of brain. The receptor dissociation rate constants in cerebrum (k4 = 0.08-0.16 min-1; koff = 0.16-0.23 min-1) and brain vascular permeability (PS = 1.3-3.4 ml/min/g) are sufficiently high to achieve equilibrium conditions within a reasonable period of time. Graphical analysis of the data is inappropriate due to the high tissue-loss rate constant for CF in brain. From these findings, CF should be a very useful opioid receptor ligand for the estimation of the receptor binding parameters in human subjects using (18F)CF and positron emission tomography.

• OSTI ID: 5961802
• Journal Information: Journal of Cerebral Blood Flow and Metabolism; (USA), Journal Name: Journal of Cerebral Blood Flow and Metabolism; (USA) Vol. 11:2; ISSN 0271-678X; ISSN JCBMD
• Country of Publication: United States
• Language: English

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59 BASIC BIOLOGICAL SCIENCES
62 RADIOLOGY AND NUCLEAR MEDICINE
ANIMALS
AUTONOMIC NERVOUS SYSTEM AGENTS
AUTORADIOGRAPHY
BIOCHEMICAL REACTION KINETICS
BIOLOGICAL MODELS
BLOOD-BRAIN BARRIER
BODY
BRAIN
CENTRAL NERVOUS SYSTEM
COMPUTERIZED TOMOGRAPHY
DIAGNOSTIC TECHNIQUES
DISTRIBUTION
DRUGS
EMISSION COMPUTED TOMOGRAPHY
ENDORPHINS
HYDROGEN COMPOUNDS
KINETICS
MAMMALS
MEMBRANE PROTEINS
MEMBRANE TRANSPORT
NERVOUS SYSTEM
NEUROREGULATORS
ORGANIC COMPOUNDS
ORGANS
PERMEABILITY
POSITRON COMPUTED TOMOGRAPHY
PROTEINS
RATS
REACTION KINETICS
RECEPTORS
RODENTS
TISSUE DISTRIBUTION
TOMOGRAPHY
TRITIUM COMPOUNDS
VERTEBRATES