Data-Driven Motion Detection and Characterization in PET Brain Scans Using List Mode

Head motion during a Positron Emission Tomography (PET) brain scan can considerably degrade image quality. External motion-tracking devices have proven successful in minimizing this effect, but the associated time, maintenance, and workflow changes inhibit their widespread clinical use. List-mode PET acquisition allows for the retroactive analysis of coincidence events on any time scale throughout a scan, and therefore potentially offers a data-driven motion detection and characterization technique. An algorithm was developed to parse list-mode data, divide the full acquisition into short scan intervals, and calculate the line-of-response (LOR) midpoint average for each interval. These LOR midpoint averages, known as “radioactivity centroids,” were presumed to represent the center of the radioactivity distribution in the scanner, and it was thought that changes in this metric over time would correspond to intra-scan motion.

Several scans were taken of the 3D Hoffman brain phantom on a GE Discovery IQ PET/CT scanner to test the ability of the radioactivity to indicate intra-scan motion. Each scan incrementally surveyed motion in a different degree of freedom (2 translational and 2 rotational). The radioactivity centroids calculated from these scans correlated linearly to phantom positions/orientations. Centroid measurements over 1-second intervals performed on scans with ~1mCi of activity in the center of the field of view had standard deviations of 0.026 cm in the x- and y-dimensions and 0.020 cm in the z-dimension, which demonstrates high precision and repeatability in this metric. Radioactivity centroids are thus shown to successfully represent discrete motions on the submillimeter scale. It is also shown that while the radioactivity centroid can precisely indicate the amount of motion during an acquisition, it fails to distinguish what type of motion occurred.

The Synthesis of Novel N-Heterocyclic Scaffolds and Diazirine-Based Molecular Tags

N-Heterocycles are ubiquitous in biologically active natural products and pharmaceuticals. Yet, new syntheses and modifications of N-heterocycles are continually of interest for the purposes of expanding chemical space, finding quicker synthetic routes, better pharmaceuticals, and even new handles for molecular labeling. There are several iterations of molecular labeling; the decision of where to place the label is as important as of which visualization technique to emphasize.

Piperidine and indole are two of the most widely distributed N-heterocycles and thus were targeted for synthesis, functionalization, and labeling. The major functionalization of these scaffolds should include a nitrogen atom, while the inclusion of other groups will expand the utility of the method. Towards this goal, ease of synthesis and elimination of step-wise transformations are of the utmost concern. Here, the concept of electrophilic amination can be utilized as a way of introducing complex secondary and tertiary amines with minimal operations.

Molecular tags should be on or adjacent to an N-heterocycle as they are normally the motifs implicated at the binding site of enzymes and receptors. The labeling techniques should be useful to a chemical biologist, but should also in theory be useful to the medical community. The two types of labeling that are of interest to a chemist and a physician would be positron emission tomography (PET) and magnetic resonance imaging (MRI).

Coincidentally, the 3-positions of both piperidine and indole are historically difficult to access and modify. However, using electrophilic amination techniques, 3-functionalized piperidines can be synthesized in good yields from unsaturated amines. In the same manner, 3-labeled piperidines can be obtained; the piperidines can either be labeled with an azide for biochemical research or an 18F for PET imaging research. The novel electrophiles, N-benzenesulfonyloxyamides, can be reacted with indole in one of two ways: 3-amidation or 1-amidomethylation, depending on the exact reaction conditions. Lastly, a novel, hyperpolarizable 15N2-labeled diazirine has been developed as an exogenous and versatile tag for use in magnetic resonance imaging.