Participants
This study was approved by the Institutional Review Board of the National Institutes for Quantum Science and Technology and was performed in accordance with the ethical standards of the 1964 Declaration of Helsinki and its later amendments. Written informed consent was obtained from all participants. One female and one male healthy volunteer were enrolled for each ligand, 18F-SPAL-T-06 (body weight 58.0 and 68.2 kg respectively, both 63 years of age) and 18F-C05-05 (body weight 56.4 and 69.1 kg, age 63 and 73 years, respectively). The same female subject participated in the studies of both ligands. Apart from a history of cholecystectomy in the male subject of 18F-C05-05, all subjects were free of medical or neuropsychiatric illnesses according to their medical history, physical examination, urinalysis, and blood tests including haematological parameters and blood biochemical test. Blood tests were repeated after the scan, and urine was also collected during the scan for pharmacokinetic measurements.
PET scans
After a single intravenous injection of either 18F-SPAL-T-06 (179.6 MBq and 182.4 MBq) or 18F-C05-05 (183.4 MBq and 173.3 MBq), 3-dimensional serial PET images were acquired with a Biograph mCT flow system (Siemens Healthcare; matrix size 400 × 400 × 575; voxel size [mm] 2 × 2 × 2). Individual injected doses are shown in Table 1. Dynamic PET scans of each subject were performed on a continuously moving bed from head to upper thigh, consisting of three imaging sessions with a 90-minute break between sessions (1.3–10 mm/s for 1,150-mm field of view, 17 frames: 115 s × 3, 230 s × 2, 460 s × 3, 884.6 s × 5 frames for the first 120-min session, and 884.6 s × 2 frames for the second and third 30-min sessions).
All PET images were reconstructed with a filtered back-projection (FBP) algorithm with a Hanning filter (4.0 mm full-width at half-maximum) and were corrected for attenuation based on CT images, for randoms using the delayed coincidence counting method, and for scatter using the single-scatter simulation method.
Image analyses
Source organs were visually identified on the PET images, including the brain, thyroid, lungs, heart, liver, spleen, stomach, pancreas, kidneys, biliary tract, small intestine, large intestine, urinary bladder, and skeleton. For each subject, regions of interest (ROIs) on source organs were drawn on a slice-by-slice basis on CT images registered with the PET images and adjusted to visually circumscribe most of the activity within the respective source organ of the PET images. CT images acquired prior to each of the three sessions were used as reference for the corresponding frames. As for each organ except for the biliary tract, intestines, and urinary bladder, we chose the most visible frame to adjust the ROI and applied it to the remaining frames. For the biliary tract, intestines, and urinary bladder, ROIs were drawn frame-by-frame on the PET images. For the skeleton, ROIs were drawn only on the bodies of the lumbar vertebrae. Images were analysed using PMOD 4.402 software (PMOD Technologies, Zurich, Switzerland).
Residence time calculations
The calculation of residence time was based on a previously reported method19. The residence time in each source organ was calculated as the area under the curve (AUC) of the time-activity curve, which was created after removing the decay correction and expressed as a percentage of injected activity (%IA) after applying a recovery correction. The time-activity curves were created with time information that was estimated from the starting time of each frame and the distance from the top of the field-of-view to the centre of each ROI divided by the bed speed of each frame. The AUC to the end of imaging was calculated by the trapezoidal method, and from the end to infinity was calculated by assuming that further decline in radioactivity occurred only by physical decay without any biological clearance. This assumption should not introduce any significant bias as the activity was very minor at the last time point, which was approximately 360 min or more than three half-lives after the injection.
The residence time of all red marrow in the body was estimated from that in the lumbar vertebrae. To estimate the absorbed radiation doses conservatively, we assigned all radioactivity in the lumbar vertebrae to red marrow. Because the mass of red marrow in the lumbar vertebrae is 12.3% of the mass of all red marrow in the body (ICRP Publication 89), the residence time in red marrow in the entire body was calculated by multiplying that of the lumbar vertebrae by 100/12.3.
The residence time of the urinary bladder wall was calculated by applying the dynamic urinary bladder model20 to the combined data from images and urine samples. The decay-corrected cumulative urinary activity from all subjects was fit to a biexponential curve. The residence time was calculated on the basis of 2.4-h voiding intervals.
To calculate the residence time of the remainder of the body, the residence time of all source organs was summed up and subtracted from the fixed theoretical value of T1/2 / ln 2, which equals 2.640 h for18F.
Estimation of absorbed dose
The absorbed radiation doses for both female and male subjects were calculated using the Medical Internal Radiation Dose scheme by entering the residence times into OLINDA/EXM 2.2 software (Hermes Medical Solutions, Stockholm, Sweden) according to the ICRP 89 models for adult females and males. Then, effective doses were calculated in OLINDA/EXM based on the recommendation in ICRP Publication 103. Mean effective doses of female and male subjects were reported.
