In vivo imaging of a v b 3 expression has important diagnostic and therapeutic applications. Multimeric cyclic RGD peptides are capable of improving the integrin a v b 3 -binding affinity due to the polyvalency effect. Here we report an example of 18 F-labeled tetrameric RGD peptide for PET of a v b 3 expression in both xenograft and spontaneous tumor models. Methods: The tetrameric RGD peptide EfE[c(RGDyK)] 2 g 2 was derived with amino-3,6,9-trioxaundecanoic acid (mini-PEG; PEG is poly(ethylene glycol)) linker through the glutamate a-amino group. NH 2 -mini-PEG-EfE[c(RGDyK)] 2 g 2 (PRGD4) was labeled with 18 F via the N-succinimidyl-4-18 F-fluorobenzoate ( 18 F-SFB) prosthetic group. The receptor-binding characteristics of the tetrameric RGD peptide tracer 18 F-FPRGD4 were evaluated in vitro by a cell-binding assay and in vivo by quantitative microPET imaging studies. Results: The decay-corrected radiochemical yield for 18 F-FPRGD4 was about 15%, with a total reaction time of 180 min starting from 18 F-F 2 . The PEGylation had minimal effect on integrin-binding affinity of the RGD peptide. 18 F-FPRGD4 has significantly higher tumor uptake compared with monomeric and dimeric RGD peptide tracer analogs. The receptor specificity of 18 F-FPRGD4 in vivo was confirmed by effective blocking of the uptake in both tumors and normal organs or tissues with excess c(RGDyK). Conclusion: The tetrameric RGD peptide tracer 18 F-FPRGD4 possessing high integrin-binding affinity and favorable biokinetics is a promising tracer for PET of integrin a v b 3 expression in cancer and other angiogenesis related diseases.

Purpose-In vivo imaging of α v β 3 has important diagnostic and therapeutic applications. 18 FGalacto-arginine-glycine-aspartic acid (RGD) has been developed for positron emission tomography (PET) imaging of integrin α v β 3 expression and is now being tested on humans. Dimerization and multimerization of cyclic RGD peptides have been reported to improve the integrin α v β 3 -binding affinity due to the polyvalency effect. Here, we compared a number of new dimeric RGD peptide tracers with the clinically used 18 F-galacto-RGD.Procedures-RGD monomers and dimers were coupled with galacto or PEG 3 linkers, and labeled with 18 F using 4-nitrophenyl 2-18 F-fluoropropionate ( 18 F-NFP) or N-succinimidyl 4-18 Ffluorobenzoate as a prosthetic group. The newly developed tracers were evaluated by cell-based receptor-binding assay, biodistribution, and small-animal PET studies in a subcutaneous U87MG glioblastoma xenograft model.

Purpose-We have previously reported that 18 F-FB-E[c(RGDyK)] 2 ( 18 F-FRGD2) allows quantitative PET imaging of integrin α v β 3 expression. However, the potential clinical translation was hampered by the relatively low radiochemical yield. The goal of this study was to improve the radiolabeling yield, without compromising the tumor targeting efficiency and in vivo kinetics, by incorporating a hydrophilic bifunctional mini-PEG spacer.

Glu-NH-CO-NH-Lys-(Ahx)-[ 68 Ga(HBED-CC)] ( 68 Ga-PSMA-11) is a PET tracer that can detect prostate cancer relapses and metastases by binding to the extracellular domain of PSMA. 68 Ga-labeled DOTA-4-amino-1-carboxymethyl-piperidine-D-Phe-Gln-Trp-AlaVal-Gly-His-Sta-Leu-NH2 ( 68 Ga-RM2) is a synthetic bombesin receptor antagonist that targets gastrin-releasing peptide receptors. We present pilot data on the biodistribution of these PET tracers in a small cohort of patients with biochemically recurrent prostate cancer. Methods: Seven men (mean age ± SD, 74.3 ± 5.9 y) with biochemically recurrent prostate cancer underwent both 68 Ga-PSMA-11 PET/ CT and 68 Ga-RM2 PET/MRI scans. SUV max and SUV mean were recorded for normal tissues and areas of uptake outside the expected physiologic biodistribution. Results: All patients had a rising level of prostate-specific antigen (mean ± SD, 13.5 ± 11.5) and noncontributory results on conventional imaging. 68 Ga-PSMA-11 had the highest physiologic uptake in the salivary glands and small bowel, with hepatobiliary and renal clearance noted, whereas 68 Ga-RM2 had the highest physiologic uptake in the pancreas, with renal clearance noted. Uptake outside the expected physiologic biodistribution did not significantly differ between 68 Ga-PSMA-11 and 68 Ga-RM2; however, 68 Ga-PSMA-11 localized in a lymph node and seminal vesicle in a patient with no abnormal 68 Ga-RM2 uptake. Abdominal periaortic lymph nodes were more easily visualized by 68 Ga-RM2 in two patients because of lack of interference by radioactivity in the small intestine. Conclusion: 68 Ga-PSMA-11 and 68 Ga-RM2 had distinct biodistributions in this small cohort of patients with biochemically recurrent prostate cancer. Additional work is needed to understand the expression of PSMA and gastrinreleasing peptide receptors in different types of prostate cancer.

The cell adhesion molecule integrin alpha vbeta 3 plays a key role in tumor angiogenesis and metastasis. A series of (18)F-labeled RGD peptides have been developed for PET of integrin expression based on primary amine reactive prosthetic groups. In this study, we report the use of the Cu(I)-catalyzed Huisgen cycloaddition, also known as a click reaction, to label RGD peptides with (18)F by forming 1,2,3-triazoles. Nucleophilic fluorination of a toluenesulfonic alkyne provided (18)F-alkyne in high yield (nondecay-corrected yield: 65.0 +/- 1.9%, starting from the azeotropically dried (18)F-fluoride), which was then reacted with an RGD azide (nondecay-corrected yield: 52.0 +/- 8.3% within 45 min including HPLC purification). The (18)F-labeled peptide was subjected to microPET studies in murine xenograft models. Murine microPET experiments showed good tumor uptake (2.1 +/- 0.4%ID/g at 1 h postinjection (p.i.)) with rapid renal and hepatic clearance of (18)F-fluoro-PEG-triazoles-RGD 2 ( (18)F-FPTA-RGD2) in a subcutaneous U87MG glioblastoma xenograft model (kidney 2.7 +/- 0.8%ID/g; liver 1.9 +/- 0.4%ID/g at 1 h p.i.). Metabolic stability of the newly synthesized tracer was also analyzed (intact tracer ranging from 75% to 99% at 1 h p.i.). In brief, the new tracer (18)F-FPTA-RGD2 was synthesized with high radiochemical yield and high specific activity. This tracer exhibited good tumor-targeting efficacy and relatively good metabolic stability, as well as favorable in vivo pharmacokinetics. This new (18)F labeling method based on click reaction may also be useful for radiolabeling of other biomolecules with azide groups in high yield.