Pilot pharmacokinetic and dosimetric studies of (18)F-FPPRGD2: a PET radiopharmaceutical agent for imaging α(v)β(3) integrin levels

Abstract

Purpose: To assess the safety, biodistribution, and dosimetric properties of the positron emission tomography (PET) radiopharmaceutical agent fluorine 18 ((18)F) FPPRGD2 (2-fluoropropionyl labeled PEGylated dimeric RGD peptide [PEG3-E{c(RGDyk)}2]), which is based on the dimeric arginine-glycine-aspartic acid (RGD) peptide sequence and targets α(v)β(3) integrin, in the first volunteers imaged with this tracer.

Materials and methods: The protocol was approved by the institutional review board, and written informed consent was obtained from all participants. Five healthy volunteers underwent whole-body combined PET-computed tomography 0.5, 1.0, 2.0, and 3.0 hours after tracer injection (mean dose, 9.5 mCi ± 3.4 [standard deviation] [351.5 MBq ± 125.8]; mean specific radioactivity, 1200 mCi/mmol ± 714 [44.4 GBq/mmol ± 26.4]). During this time, standard vital signs, electrocardiographic (ECG) readings, and blood sample values (for chemistry, hematologic, and liver function tests) were checked at regular intervals and 1 and 7 days after the injection. These data were used to evaluate tracer biodistribution and dosimetric properties, time-activity curves, and the stability of laboratory values. Significant changes in vital signs and laboratory values were evaluated by using a combination of population-averaged generalized estimating equation regression and exact paired Wilcoxon tests.

Results: The administration of (18)F-FPPRGD2 was well tolerated, with no marked effects on vital signs, ECG readings, or laboratory values. The tracer showed the same pattern of biodistribution in all volunteers: primary clearance through the kidneys (0.360 rem/mCi ± 0.185 [0.098 mSv/MBq ± 0.050]) and bladder (0.862 rem/mCi ± 0.436 [0.233 mSv/MBq ± 0.118], voiding model) and uptake in the spleen (0.250 rem/mCi ± 0.168 [0.068 mSv/MBq ± 0.046]) and large intestine (0.529 rem/mCi ± 0.236 [0.143 mSv/MBq ± 0.064]). The mean effective dose of (18)F-FPPRGD2 was 0.1462 rem/mCi ± 0.0669 (0.0396 mSv/MBq ± 0.0181). With an injected dose of 10 mCi (370 MBq) and a 1-hour voiding interval, a patient would be exposed to an effective radiation dose of 1.5 rem (15 mSv). Above the diaphragm, there was minimal uptake in the brain ventricles, salivary glands, and thyroid gland. Time-activity curves showed rapid clearance from the vasculature, with a mean 26% ± 17 of the tracer remaining in the circulation at 30 minutes and most of the activity occurring in the plasma relative to cells (mean whole blood-plasma ratio, 0.799 ± 0.096).

Conclusion: (18)F-FPPRGD2 has desirable pharmacokinetic and biodistribution properties. The primary application is likely to be PET evaluation of oncologic patients-especially those with brain, breast, or lung cancer. Specific indications may include tumor staging, identifying patients who would benefit from antiangiogenesis therapy, and separating treatment responders from nonresponders early.

Figures

Figure 1:

Chemical structure of 18F-FPPRGD2. Arg = arginine, Asp = aspartic acid, Gly = glycine, Lys = lysine.

Figure 2:

A, Coronal maximum intensity projection PET image shows distribution of 18F-FPPRGD2 1 hour after intravenous administration in healthy volunteer (subject 1). Principal organs and regions of uptake are labeled: brain ventricles (1), salivary-oropharyngeal cavity (2), thyroid gland (3), lungs (4), liver (5), spleen (6), kidneys (7), bowel (8), and bladder (9). B, Corresponding axial CT (left) and PET (right) images further show distribution of 18F-FPPRGD2 at key levels in brain (top), thorax (middle), and upper abdomen (bottom). Principal organs and regions of uptake are labeled: brain ventricles, brain (10), lungs, liver, spleen, kidneys, heart (11), and stomach (12).

Figure 3a:

PET image sets show temporal and intersubject stability of 18F-FPPRGD2. All images are coronal views of maximum intensity projection images from PET examination. (a) Images show tracer uptake in 58-year-old women (volunteer 2) at five time points after 18F-FPPRGD2 injection. (b) Images show uptake differences among the five subjects 1 hour after injection. There is minimal variability in 18F-FPPRGD2 uptake over time and across subjects.

Figure 3b:

PET image sets show temporal and intersubject stability of 18F-FPPRGD2. All images are coronal views of maximum intensity projection images from PET examination. (a) Images show tracer uptake in 58-year-old women (volunteer 2) at five time points after 18F-FPPRGD2 injection. (b) Images show uptake differences among the five subjects 1 hour after injection. There is minimal variability in 18F-FPPRGD2 uptake over time and across subjects.

Figure 4a:

Averaged time-activity curves indicate clearance of 18F-FPPRGD2 from (a) bladder, (b) intestines, (c) liver, and (d) kidneys and percentages of total injected activity in each organ versus time after tracer injection, for all healthy volunteers. Activity data are not decay corrected to the time of injection. Error bars indicate standard deviations.

Figure 4b:

Averaged time-activity curves indicate clearance of 18F-FPPRGD2 from (a) bladder, (b) intestines, (c) liver, and (d) kidneys and percentages of total injected activity in each organ versus time after tracer injection, for all healthy volunteers. Activity data are not decay corrected to the time of injection. Error bars indicate standard deviations.

Figure 4c:

Averaged time-activity curves indicate clearance of 18F-FPPRGD2 from (a) bladder, (b) intestines, (c) liver, and (d) kidneys and percentages of total injected activity in each organ versus time after tracer injection, for all healthy volunteers. Activity data are not decay corrected to the time of injection. Error bars indicate standard deviations.

Figure 4d:

Averaged time-activity curves indicate clearance of 18F-FPPRGD2 from (a) bladder, (b) intestines, (c) liver, and (d) kidneys and percentages of total injected activity in each organ versus time after tracer injection, for all healthy volunteers. Activity data are not decay corrected to the time of injection. Error bars indicate standard deviations.

Figure 5:

Time-activity curves for 18F-FPPRGD2 in whole blood (◆) and plasma (■), for all healthy volunteers. Error bars indicate standard deviations. 18F-FPPRGD2 clears from blood rapidly, with most activity in plasma portion.