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

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)ß(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.

First experience with clinical-grade ([18F]FPP(RGD2): an automated multi-step radiosynthesis for clinical PET studies.

PURPOSE: A reliable and routine process to introduce a new ¹8F-labeled dimeric RGD-peptide tracer ([¹8F]FPP(RGD2) for noninvasive imaging of α(v)ß3 expression in tumors needed to be developed so the tracer could be evaluated for the first time in man. Clinical-grade [¹8F]FPP(RGD)2 was screened in mouse prior to our first pilot study in human. PROCEDURES: [¹8F]FPP(RGD)2 was synthesized by coupling 4-nitrophenyl-2-[¹8F]fluoropropionate ([¹8F]NPE) with the dimeric RGD-peptide (PEG3-c(RGDyK)2). Imaging studies with [¹8F]FPP(RGD)2 in normal mice and a healthy human volunteer were carried out using small animal and clinical PET scanners, respectively. RESULTS: Through optimization of each radiosynthetic step, [¹8F]FPP(RGD)2 was obtained with RCYs of 16.9 ± 2.7% (n = 8, EOB) and specific radioactivity of 114 ± 72 GBq/µmol (3.08 ± 1.95 Ci/µmol; n = 8, EOB) after 170 min of radiosynthesis. In our mouse studies, high radioactivity uptake was only observed in the kidneys and bladder with the clinical-grade tracer. Favorable [¹8F]FPP(RGD)2 biodistribution in human studies, with low background signal in the head, neck, and thorax, showed the potential applications of this RGD-peptide tracer for detecting and monitoring tumor growth and metastasis. CONCLUSIONS: A reliable, routine, and automated radiosynthesis of clinical-grade [¹8F]FPP(RGD)2 was established. PET imaging in a healthy human volunteer illustrates that [¹8F]FPP(RGD)2 possesses desirable pharmacokinetic properties for clinical noninvasive imaging of α(v)ß3 expression. Further imaging studies using [¹8F]FPP(RGD)2 in patient volunteers are now under active investigation.