Radiochemistry devoted to the production of monoamine oxidase (MAO-A and MAO-B) ligands for brain imaging with positron emission tomography

This article describes the kinetic modeling of [11C]SL25.1188 ([(S)-5-methoxymethyl-3-[6-(4,4,4-trifluorobutoxy)-benzo[ d]isoxazol-3-yl]-oxazolidin-2-[11C]one]) binding to monoamine oxidase B (MAO-B) in the human brain using high-resolution positron emission tomography (PET). Seven healthy subjects underwent two separate 90-minute PET scans after an intravenous injection of [11C]SL25.1188. Complementary arterial blood sampling was acquired. Radioactivity was quickly eliminated from plasma with 80% of parent compound remaining at 90 minutes. Metabolites were more polar than the parent compound. Time-activity curves showed high brain uptake, early peak and washout rate consistent with known regional MAO-B concentration. A two-tissue compartment model (2-TCM) provided better fits to the data than a 1-TCM. Measurement of total distribution volume ( VT) showed very good identifiability (based on coefficient of variation (COV)) for all regions of interest (ROIs) (COV( VT)<8%), low between-subject variability (˜20%), and quick temporal convergence (within 5% of final value at 45 minutes). Logan graphical method produces very good estimation of VT. Regional VT highly correlated with previous postmortem report of MAO-B level ( r2 = ≤0.9). Specific binding would account from 70% to 90% of VT. Hence, VT measurement of [11C]SL25.1 188 PET is an excellent estimation of MAO-B concentration.

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Measurement of Cerebral Monoamine Oxidase B Activity Using L-[11C]Deprenyl and Dynamic Positron Emission Tomography

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.1991.103 ◽

1991 ◽

Vol 11 (4) ◽

pp. 545-556 ◽

Cited By ~ 50

Author(s):

A. A. Lammertsma ◽

C. J. Bench ◽

G. W. Price ◽

J. E. Cremer ◽

S. K. Luthra ◽

...

Keyword(s):

Positron Emission Tomography ◽

Monoamine Oxidase ◽

Regional Analysis ◽

Emission Tomography ◽

Type B ◽

Irreversible Binding ◽

Mao B ◽

Positron Emission ◽

Tracer Kinetic ◽

Tissue Compartments

A tracer kinetic procedure was developed for the measurement of monoamine oxidase type B (MAO-B) activity using L-[11C]deprenyl and positron emission tomography (PET). The kinetic model consisted of two tissue compartments with irreversible binding to the second compartment (three rate constants). In addition, a blood volume component was included. Special attention was given to the accurate measurement of the plasma and whole blood input functions. The method was applied to the measurement of the dose-response curve of a reversible MAO-B inhibitor (Ro 19–6327). From the results, it followed that the rate constant for irreversible binding ( k3) appeared to be a better index of MAO-B activity than the net influx constant Ki Furthermore, regional analysis demonstrated that Ki but not k3, was flow dependent. This implies that full kinetic analysis is required for an accurate assessment of MAO-B activity.

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Dynamic, Adaptive Changes in MAO-A Binding after Alterations in Substrate Availability: An in vivo [11C]-Harmine Positron Emission Tomography Study

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2011.184 ◽

2011 ◽

Vol 32 (3) ◽

pp. 443-446 ◽

Cited By ~ 20

Author(s):

Julia Sacher ◽

Eugenii A Rabiner ◽

Michael Clark ◽

Pablo Rusjan ◽

Alexandra Soliman ◽

...

Keyword(s):

Positron Emission Tomography ◽

Monoamine Oxidase ◽

Monoamine Oxidase A ◽

Emission Tomography ◽

Tryptophan Depletion ◽

Major Depressive ◽

Positron Emission ◽

Mao A ◽

Adaptive Role

Monoamine oxidase A (MAO-A) is an important target in the pathophysiology and therapeutics of major depressive disorder, aggression, and neurodegenerative conditions. We measured the effect of changes in MAO-A substrate on MAO-A binding in regions implicated in affective and neurodegenerative disease with [11C]-harmine positron emission tomography in healthy volunteers. Monoamine oxidase A VT, an index of MAO-A density, was decreased (mean: 14%±9%) following tryptophan depletion in prefrontal cortex ( P<0.031), and elevated (mean: 17%±11%) in striatum following carbidopa—levodopa administration ( P<0.007). These findings suggest an adaptive role for MAO-A in maintaining monoamine neurotransmitter homeostasis by rapidly compensating fluctuating monoamine levels.

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