Evaluation of [18F]MNI-792 as PET tracer for Brain cholesterol 24 hydroxylase in Healthy Volunteers

Objectives: This Phase 1 clinical trial aimed to (1) assess dynamic brain uptake of [18F]MNI-792 targeting the cholesterol 24-hydroxylase (CH24H) enzyme; (2) compare invasive vs. noninvasive tracer kinetic modeling to quantitatively analyze brain CH24H levels; (3) obtain test/retest reproducibility; and (4) determine safety, biodistribution and radiation absorbed dose burden in healthy volunteers. Methods: Six subjects had two [18F]MNI-792 dynamic brain PET scans up to 3 weeks apart. Additionally, 5 subjects underwent a single whole-body PET scan to determine biodistribution.Subjects were administered a single dose of 326 ± 37 MBq (8.8 ± 1.0 mCi) of [18F]MNI-792 intravenously. Serial 3D PET images were acquired on a Siemens ECAT EXACT HR+ camera over 3.5 hours. The PET data were analyzed with the 1-tissue (1T) and 2-tissue (2T) compartment model as well as Logan graphical analysis (LGA), using the metabolite corrected arterial plasma input function, to calculate total distribution volume VT. Binding potential (BPND) was derived indirectly from VT by using the cerebellum as a reference. BPND was also estimated directly by the non-invasive version of Logan graphical analysis (NI-LOA), and the simplified reference tissue model (SRTM) using the cerebellum as a reference.Whole body imaging studies were performed on a Siemens HR+ PET camera to determine the biodistribution of [18F]MNI-792 and to estimate radiation absorbed doses to source organs and whole body. Subjects received 340.2 ± 14.9 MBq (9 .2 ± 0.4 mCi) of [18F]MNI-792 iv. Organ residence times for brain, heart, liver, gallbladder, and kidneys were computed from area under the non-decay corrected time activity curves. The ICRP 30 gastrointestinal tract model was applied to compute residence times in the small intestine, lower and upper large intestine. Organ Level Internal Dose Assessment (OLINDA) EXM 1.1 software package was used to estimate the organ and whole-body radiation absorbed doses. Results: There were no clinically significant changes in vital signs, ECG or laboratory values. Highest uptake was observed in putamen, followed by caudate, anterior cingulate, nucleus accumbens, globus palidus and other cortical regions. The average test/retest variability across the six subjects was 10-15% for VT, while the variability for BPND was 5-10%.Elimination was via hepatobiliary and urinary routes, with a maximum of 20.0 ± 8.4 %ID in the liver and 33.5 ± 5.1 %ID in the intestine. The gallbladder was the