The Biodistribution and Radiation Dosimetry of the Arg-Gly-Asp Peptide ¹⁸F-AH111585 in Healthy Volunteers

Radiopharmaceutical Preparation

Synthesis of the agent has been described previously (6,8).

Subjects

Approval for this study was received from the Hammersmith Hospitals NHS Trust Research Ethics Committee, the Administration of Radioactive Substances Advisory Committee, and the Medicines and Healthcare Products Regulatory Agency. Eight healthy volunteers (5 men, 3 women), with an age of 61 ± 4 y and body mass index of 27.2 ± 2.8 kg/m², were recruited. Inclusion criteria included age between 50 and 65 y, ability to provide informed written consent, and normal medical history (including physical examination, electrocardiogram, hematology, and biochemistry). Exclusion criteria included pregnancy and lactation.

Safety

Safety data collected up to 72 h after injection included adverse events (AEs); vital signs (blood pressure, respiratory rate, heart rate, and body temperature); physical examination; cardiovascular, lung, abdomen, and neurologic examinations; electrocardiogram; and laboratory parameters (serum biochemistry, hematology, coagulation, and urinalysis). Blood samples were collected through an indwelling catheter, and to avoid occlusion, heparinized saline was used for line flushing.

Image Acquisition and In Vivo Activity Measurement

Images were acquired with a 962 EXACT HR+ PET scanner (CTI/Siemens) with 15.5-cm axial and 58-cm transaxial fields of view. Before administration of ¹⁸F-AH111585, a transmission scan of each subject was performed using ⁶⁸Ge sources to provide attenuation maps. A whole-torso emission scan consisted of contiguous static images acquired at 6 bed positions, with the inferior border set to include the urinary bladder within the field of view and the superior border set at approximately the level of the epiglottis or above. The total axial length of the concatenated image was 81 cm, and ¹⁸F activity in the anatomy outside the field of view (part of the head and lower extremities) was assumed uniformly distributed and equal to the difference between that administered and measured in the imaged anatomy.

The mean injected ¹⁸F activity in the subjects was 163.7 MBq (range, 155.2–173.1 MBq) via an antecubital vein. The mean administered AH111585 mass dose was 2.5 μg (range, 1–4.5 μg), and the mean injected volume was 3.3 mL (range, 2–5.5 mL) for a specific activity of 147 GBq/μmol (range, 69–292 GBq/μmol). Three-dimensional whole-torso acquisitions of subjects were taken at 4 time points up to 4 h after injection with nominal start times of 5, 50, 100, and 160 min after injection. To compensate for physical decay of ¹⁸F, the acquisition for each bed position increased 4, 5, 6, and 7.5 min per individual bed position for these 4 time points after injection.

Emission data were reconstructed using the ordered-subsets expectation maximization (OSEM) algorithm (6 iterations and 16 subsets) (9) and filtered backprojection (FBP) (10). Whereas OSEM-reconstructed tomographic images provided superior delineation, enabling definition of anatomic regions of interest (ROIs), phantom measurements demonstrated that FBP-reconstructed images provided more accurate quantification of ¹⁸F activity. Hence, ROIs were defined on OSEM-reconstructed images and mapped to the corresponding FBP image to extract the ¹⁸F activities using ANALYZE analysis software (version 7; Biomedical Imaging Resource, Mayo Clinic). Coronal reconstruction was used, and 256 slices for each reconstructed set were collapsed to a single plane and ROIs drawn around specific visible organs and any other structures displaying uptake. ¹⁸F activities were decay-corrected to the time of injection and normalized to the total administered activity.

ROIs included salivary glands, thyroid, lungs, heart, liver, gallbladder, spleen, gastrointestinal tract, kidneys, urinary bladder contents, and remaining tissues. The gastrointestinal tract demonstrated rapid nonspecific uptake by soft tissue that cleared while activity within the gastrointestinal tract contents was introduced through hepatobiliary drainage. To isolate both contributions, an ROI was placed over the quadriceps femoris muscle, and ¹⁸F activity washout was measured. This time–activity curve was rescaled to that of the gastrointestinal tract ROI at the first imaging time, when there was no activity in the gastrointestinal tract contents, and the result was subtracted from the total gastrointestinal tract ROI activity at subsequent time points to yield ¹⁸F activity within the gastrointestinal tract contents alone.

Measurement of In Vitro Activity

Venous blood samples were taken at nominal times of 5, 10, 15, 30, 60, 90, 150, and 240 min after injection. Dual 1-mL aliquots each of whole blood and plasma were obtained from each sample, and ¹⁸F activity concentration was measured in a well counter. Urine was collected as voided up to 240 min after injection, and the volume and time of each micturition recorded. Dual 0.1-mL aliquots of urine were sampled from each void, the mean ¹⁸F activity per aliquot was measured, and the resulting ¹⁸F activity concentration was multiplied by the volume of voided urine to provide the ¹⁸F activity excreted.

As the heart wall and blood contained within are MIRD-specified source regions, ¹⁸F activity within each region was determined by considering the activity extracted from the heart ROI as the sum of those within the cardiac wall and blood contents. The latter was estimated by the product of the measured ¹⁸F activity concentration in whole blood at the time of imaging and the sex-specific reference volumes of cardiac chamber blood (11). The measured ¹⁸F activity concentration was then subtracted from the activity in the heart ROI to isolate that in the heart wall.

Biodistribution

For each source region, the decay-corrected ¹⁸F activity over the 4 time points was least-squares-fit by an analytic function. Physical decay of ¹⁸F was incorporated and the function integrated to yield the cumulated activity (numerically equal to the residence time, the cumulated activity normalized to the administered activity is presented here in units of MBq·h/MBq to avoid confusion with temporal quantities). Cumulated activities of the contents of the small intestine, upper large intestine, and the lower large intestine were calculated using a dynamic model for the gastrointestinal tract (12) with the assumption that all activity enters the duodenum via hepatobiliary transport. The cumulated activity in the urinary bladder contents and voided urine was calculated using a dynamic urinary bladder model (13) for a 3.5-h voiding interval (14).

Internal Radiation Dosimetry

The internal radiation dosimetry for the adult human was evaluated through the normalized cumulated activities for each subject provided as input to the OLINDA/EXM code (15). The resulting ensemble of mean absorbed doses per unit administered activity was then used to calculate the effective dose per unit administered activity (16), with the following modifications: the gonadal dose as the arithmetic mean of the testicular- and ovarian-absorbed doses (14); removal of the upper large intestine wall from the remaining organ category and calculation of the colon-absorbed dose as the fractional mass-weighted sum of the mean absorbed doses to the walls of the upper and lower large intestines (17); and the thymus-absorbed dose as a surrogate for that to the esophagus (17).

The organ-absorbed doses and effective dose evaluated for each individual subject were subsequently averaged.

Safety

¹⁸F-AH111585 was found to be safe and well tolerated in all subjects. No serious AEs or drug-related AEs were reported. Two of 8 subjects had a total of 3 non–drug-related AEs, including catheter site–related reaction, headache, and dyspepsia. No other abnormalities were seen except for increase in activated partial thromboplastin time (aPTT; reference range, 20.4–31.4 s). Transient, asymptomatic increases in aPTT (up to 30.4 s above reference range) after ¹⁸F-AH111585 administration were observed in 5 of 8 subjects (62.5%). The increases in aPTT completely reversed within 24 h without any treatment and were likely due to the use of intravenous heparin flushes in the same catheter from which the aPTT samples were drawn. There was no evidence of clinical bleeding.

Biodistribution

Images of a representative male subject between 5 and 208 min after injection of ¹⁸F-AH111585 are presented in Figure 1. All subjects demonstrated initially high uptake in the liver, spleen, and heart wall. The mean initial uptake of activity in the liver was 15% ± 5%, with washout decreasing to 8% ± 2% at about 4 h after injection. The estimated ¹⁸F activity excreted through the urinary pathway and the gastrointestinal tract were 37% ± 14% and 20% ± 5%, respectively. The biologic half-life of ¹⁸F activity in whole blood was 0.25 ± 0.07 h. Table 1 provides the cumulated activities. Source regions with the 3 highest mean normalized cumulated activities (excluding remaining tissues) are those of the combined urinary bladder contents and voided urine (0.456 MBq·h/MBq for a 3.5-h voiding interval), liver (0.23 MBq·h/MBq), and gastrointestinal tract wall (0.22 MBq·h/MBq).

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FIGURE 1. 

Series of whole-torso images of representative subject showing biodistribution of ¹⁸F activity for acquisitions begun between 5 and 208 min after administration of ¹⁸F-AH111585. p.i. = after administration.

Radiation Dosimetry

Table 2 summarizes the organ- or tissue-absorbed doses. Those organs or tissues receiving the 3 highest values were the urinary bladder wall (124 μGy/MBq), kidneys (102 μGy/MBq), and cardiac wall (59 μGy/MBq). The mean effective dose was 26 μSv/MBq.