Quantitative Analysis and Comparison Study of [18F]AlF-NOTA-PRGD2, [18F]FPPRGD2 and [68Ga]Ga-NOTA-PRGD2 Using a Reference Tissue Model

Abstract

With favorable pharmacokinetics and binding affinity for αvβ3 integrin, 18F-labeled dimeric cyclic RGD peptide ([18F]FPPRGD2) has been intensively used as a PET imaging probe for lesion detection and therapy response monitoring. A recently introduced kit formulation method, which uses an 18F-fluoride-aluminum complex labeled RGD tracer ([18F]AlF-NOTA-PRGD2), provides a strategy for simplifying the labeling procedure to facilitate clinical translation. Meanwhile, an easy-to-prepare 68Ga-labeled NOTA-PRGD2 has also been reported to have promising properties for imaging integrin αvβ3. The purpose of this study is to quantitatively compare the pharmacokinetic parameters of [18F]FPPRGD2, [18F]AlF-NOTA-PRGD2, and [68Ga]Ga-NOTA-PRGD2. U87MG tumor-bearing mice underwent 60-min dynamic PET scans following the injection of three tracers. Kinetic parameters were calculated using Logan graphical analysis with reference tissue. Parametric maps were generated using voxel-level modeling. All three compounds showed high binding potential (BpND = k3/k4) in tumor voxels. [18F]AlF-NOTA-PRGD2 showed comparable BpND value (3.75±0.65) with those of [18F]FPPRGD2 (3.39±0.84) and [68Ga]Ga-NOTA-PRGD2 (3.09±0.21) (p>0.05). Little difference was found in volume of distribution (VT) among these three RGD tracers in tumor, liver and muscle. Parametric maps showed similar kinetic parameters for all three tracers. We also demonstrated that the impact of non-specific binding could be eliminated in the kinetic analysis. Consequently, kinetic parameter estimation showed more comparable results among groups than static image analysis. In conclusion, [18F]AlF-NOTA-PRGD2 and [68Ga]Ga-NOTA-PRGD2 have comparable pharmacokinetics and quantitative parameters compared to those of [18F]FPPRGD2. Despite the apparent difference in tumor uptake (%ID/g determined from static images) and clearance pattern, the actual specific binding component extrapolated from kinetic modeling appears to be comparable for all three dimeric RGD tracers.

Evaluation of synovial angiogenesis in patients with rheumatoid arthritis using 68Ga-PRGD2 PET/CT: a prospective proof-of-concept cohort study

“…68 Ga-PRGD2 is specifically designed to target the endothelial cells of neovasculature that express α v β 3 -integrin at high levels 17 18. Therefore, 68 Ga-PRGD2 PET/CT represents a specific method for evaluating angiogenesis.…”

Principles in the design of ligand-targeted cancer therapeutics and imaging agents

“…SSTR2-targeted radiotherapeutics that use lutetium-177 and yttrium-90 are also currently under evaluation 192,193 . Other notable targeted imaging agents in clinical trials include: 111 In-exendin-4, which targets glucagon-like peptide 1 receptor and is being tested for imaging insulinomas (NCT02127541 and NCT00937079) 194 ; NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid)-(PEGylated arginine-glycine-aspartic acid dimer) PRGD2 and fluciclatide, which target α v β 3 integrin and are being tested in lung cancer (NCT01527058) [195][196][197][198][199][200] ; 18 F-VM4-037, an imaging agent that has completed Phase II trials in kidney cancer (NCT01712685) and targets carbonic anhydrase 9, which is overexpressed in hypoxic tumours; and BAY86-7548, a 68 Ga- …”

Al18F labeling of peptides and proteins

“…A similar approach was used by a group at the National Institutes of Health. [23][24][25] They conjugated NOTA to RGD 2 via a short PEG-linker (NOTA-PRGD 2 ). Biodistribution and PET imaging in U87MG glioma tumor-bearing mice was compared with 68 Ga-NOTA-PRGD 2 F-FDG imaging.…”