Classics in Neuroimaging: Development of Positron Emission Tomography Tracers for Imaging the GABAergic Pathway.

Advances in drug discovery and diverse radiochemical methodologies have led to the discovery of novel positron emission tomography (PET) radiotracers used to image the GABAergic system, shaping our fundamental understanding of a variety of brain health illnesses, including epilepsy, stroke, cerebral palsy, schizophrenia, autism, Alzheimer's disease, and addictions. In this Viewpoint, we review the state-of-the art of PET imaging with radiotracers that target the GABAA-benzodiazepine receptor complex, challenges and opportunities for imaging GABAB receptors and GABA transporters, and highlight an ongoing need to develop more sensitive radiotracers for imaging GABA release in the central nervous system.

Identification of AV-1451 as a Weak, Nonselective Inhibitor of Monoamine Oxidase.

[18F]AV-1451 is one of the most widely used radiotracers for positron emission tomography (PET) imaging of tau protein aggregates in neurodegenerative disorders. While the radiotracer binds with high affinity to tau neurofibrillary tangles, extensive clinical studies have simultaneously revealed off-target tracer accumulation in areas of low tau burden such as the basal ganglia and choroid plexus. Though there are a number of possible reasons for this accumulation, it is often attributed to off-target binding to monoamine oxidase (MAO). In this paper, we investigate the association between [18F]AV-1451 and MAO through (i) enzyme inhibition assays, (ii) autoradiography with postmortem tissue samples, and (iii) nonhuman primate PET imaging. We confirm that [18F]AV-1451 is a weak inhibitor of MAO-A and -B and that MAO inhibitors can alter binding of [18F]AV-1451 in autoradiography and in vivo PET imaging.

Deuterium Kinetic Isotope Effect Studies of a Potential in Vivo Metabolic Trapping Agent for Monoamine Oxidase B.

Visualizing the in vivo activity of monoamine oxidase B (MAO-B) is a valuable tool in the ongoing investigation of astrogliosis in neurodegeneration. Existing strategies for imaging changes in MAO enzyme expression or activity have utilized the irreversible suicide inhibitors or high-affinity reversibly binding inhibitors as positron emission tomography (PET) ligands. As an alternative approach, we developed 4-methyl-7-[(1-[11C]methyl-1,2,3,6-tetrahydropyridin-4-yl)oxy]-2 H-chromen-2-one ([11C]Cou) as a metabolic trapping agent for MAO-B. Trapping of [11C]Cou in rhesus monkey brain demonstrated MAO-B selectivity. In this work, we have attempted to improve on the in vivo pharmacokinetics of [11C]Cou by using the deuterium kinetic isotope effect (KIE) to slow the MAO-B-mediated oxidation step and thus reduce the rate of trapping in brain tissues. However, in vitro assays of enzyme kinetics and in vivo PET imaging of pharmacokinetics in primate brain showed no effects of deuterium substitution on the tetrahydropyridine ring of [11C]Cou. The results are possibly due to masking of the KIE by a second step in the overall metabolism of the new imaging agent.

Futureproofing [18F]Fludeoxyglucose manufacture at an Academic Medical Center.

BACKGROUND: We recently upgraded our [18F]fludeoxyglucose (FDG) production capabilities with the goal of futureproofing our FDG clinical supply, expanding the number of batches of FDG we can manufacture each day, and improving patient throughput in our nuclear medicine clinic. In this paper we report upgrade of the synthesis modules to the GE FASTLab 2 platform (Phase 1) and cyclotron updates (Phase 2) from both practical and regulatory perspectives. We summarize our experience manufacturing FDG on the FASTLab 2 module with a high-yielding self-shielded niobium (Nb) fluorine-18 target. RESULTS: Following installation of Nb targets for production of fluorine-18, a 55 µA beam for 22 min generated 1330 ± 153 mCi of [18F]fluoride. Using these cyclotron beam parameters in combination with the FASTLab 2, activity yields (AY) of FDG were 957 ± 102 mCi at EOS, corresponding to 72% non-corrected AY (n = 235). Our workflow, inventory management and regulatory compliance have been greatly simplified following the synthesis module and cyclotron upgrades, and patient wait times for FDG PET have been cut in half at our nuclear medicine clinic. CONCLUSIONS: The combination of FASTlab 2 and self-shielded Nb fluorine-18 targets have improved our yield of FDG, and enabled reliable and repeatable manufacture of the radiotracer for clinical use.