Development and Clinical Application of Positron Emission Tomography Imaging Agents for Monoamine Oxidase B

Abstract

Monoamine oxidase B (MAO-B) is a high-density protein in the brain mainly found on outer mitochondrial membranes, primarily in astroglia, but additionally in serotonergic neurons and in the substantia nigra in the midbrain. It is an enzyme that participates in the oxidative metabolism of important monoamines including dopamine, norepinephrine, benzylamine, and phenylethylamine. Elevated MAO-B density may be associated with astrogliosis and inhibiting MAO-B may reduce astrogliosis. MAO-B density is elevated in postmortem sampling of pathology for many neuropsychiatric diseases including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and alcohol use disorder. Initial development of positron emission tomography (PET) imaging agents focused on analogs of [11C]L-deprenyl, with the most commonly applied being the deuterium substituted [11C]L-deprenyl-D2. This latter radiotracer was modeled with an irreversible trapping compartment reflecting its irreversible binding to MAO-B. Subsequently, [11C]SL25.1188, a reversible binding MAO-B radioligand with outstanding properties including high specific binding and excellent reversibility was developed. [11C]SL25.1188 PET was applied to discover a substantive elevation of MAO-B binding in the prefrontal cortex in major depressive disorder (MDD) with an effect size of more than 1.5. Longer duration of MDD was associated with greater MAO-B binding throughout most gray matter regions in the brain, suggesting progressive astrogliosis. Important applications of [11C]L-deprenyl-D2 PET are detecting a 40% loss in radiotracer accumulation in cigarette smokers, and substantial occupancy of novel therapeutics like EVT301 and sembragiline. Given the number of diseases with elevations of MAO-B density and astrogliosis, and the advance of [11C]SL25.1188, clinical applications of MAO-B imaging are still at an early stage.

The Role of Neuro-Immune Interactions in Chronic Pain: Implications for Clinical Practice

“…[38][39][40][41] While there are no microglia-specific radioligands, there are radioligands that are more specific for astrocytes (radioligand [11C]-L-deprenyl-D2 targets the astrocyte-specific monoamine oxidase B). 42 An interesting PET study examining fibromyalgia patients observed elevated TSPO but not [11C]-L-deprenyl-D2 signals in the frontal and parietal lobes, supporting that microglia, but not astrocytes, contribute to neuroinflammation in these patients. 43 The development of more specific PET tracers for microglia (such as targeting other receptors like P2X purinoreceptor 7; P2XR7) and tracers capable of differentiating between microglia phenotypes will help advance our clinical understanding of the dynamics of microglial activation in pain and in other neurologic diseases.…”

“… 105 The PET tracer targeting TSPO, as discussed previously, cannot distinguish between microglia and astrocytic activity, but the tracer ligand [11C]-L-deprenyl-D2 is generally accepted for the detection of astrocytes due to the selective expression of its monoamine oxidase B target. 42 , 106–108 …”

“…105 The PET tracer targeting TSPO, as discussed previously, cannot distinguish between microglia and astrocytic activity, but the tracer ligand [11C]-L-deprenyl-D2 is generally accepted for the detection of astrocytes due to the selective expression of its monoamine oxidase B target. 42,[106][107][108] Neuron to Astrocyte Interactions Different cell types likely interact with astrocytes and influence the transition to reactive astrogliosis, so it is difficult to distinguish the direct or indirect actions between the various CNS cell types and astrocytes. For example, TNFa signaling through TNFR is a major axis for astrocyte activation, and intrathecal injection of TNFa-activated astrocytes into the spinal cord is sufficient to induce pain behavior in the absence of any injury.…”

Klinischer Stellenwert der Bildgebung der Neuroinflammation

“…Der erste PET-Tracer war [ 11 C]Deprenyl, jedoch hat das hohe Hintergrundsignal aufgrund irreversibler Bindung und radioaktiver Metaboliten im gesunden Gehirn die Anwendbarkeit deutlich eingeschränkt. Neuere Studien verwenden daher reversible und selektive MAO-B Liganden wie das deuterierte [ 11 C]deuterium-L-Deprenyl, welches vielversprechende Ergebnisse zeigt [13]. Bisherige Studien weisen darauf hin, dass das Level der Astrogliose mit der bisherigen Krankheitsdauer bei neuropsychiatrischen Erkrankungen wie z.…”

“…Bisherige Studien weisen darauf hin, dass das Level der Astrogliose mit der bisherigen Krankheitsdauer bei neuropsychiatrischen Erkrankungen wie z. B. Depression korreliert, was den Anstieg der Astrogliose im Krankheitsverlauf widerspiegeln würde [13]. Die MAO-B-PET wird derzeit noch nicht regulär in der klinischen Routine angewendet, sondern lediglich in wissenschaftlichen Studien evaluiert.…”