Noninvasive PET Imaging of a Ga-68-Radiolabeled RRL-Derived Peptide in Hepatocarcinoma Murine Models

Abstract

Our study successfully prepared [Ga]DOTA-RRL with a high labeling yield under the optimized reaction conditions and demonstrated its potential role as a PET imaging agent for tumor-targeted diagnosis.

Catechol-Based Functionalizable Ligands for Gallium-68 Positron Emission Tomography Imaging

“…In a first step, the benzylprotected podand GlyCAM(Bn) (14) was synthesized in a manner similar to that of Glu( t Bu)CAM(Bn) (10) according to the procedure of Dertz et al 55 In situ N-hydroxysuccinimide (NHS) activation of the arm Glu( t Bu)CAM(Bn) (10) with Nethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC•HCl) enabled further conjugation to the tris(2aminoethyl)amine backbone to yield the monosubstituted TREN intermediate 13. In situ NHS activation of the second arm, GlyCAM(Bn) (14), enabled conjugation to the two remaining primary amines of 13 and completion of the fully protected ligand (15). Simultaneous deprotection of the tertbutyl and benzyl groups under acidic conditions yielded the final ligand 4 that was kept under N 2 (g) in the dark at 4 °C.…”

“…The volatiles were then removed under reduced pressure to yield TREN-Glu( t Bu)-CAM(Bn) (13) as a yellow paste (0.42 g, 91%) that was used immediately in the next step without further purification. 1 TREN-bisGlyGlu( t Bu)-CAM(Bn) (15). To a stirred solution of GlyCAM(Bn) (14, 0.27 g, 0.69 mmol) in anhydrous dichloromethane (10 mL) was added N-hydroxysuccinimide (NHS, 0.106 g, 0.921 mmol), and the resulting reaction mixture was cooled to 0 °C.…”

“…3 Two different approaches are pursued in the design of radiopharmaceutical imaging agents. The first involves organic molecules, often based on drugs, which incorporate a nonmetal PET radionuclide such as 11 C, 13 N, 15 O, or 18 F. 3−7 The second approach employs PET radioactive metals tightly coordinated by a chelate and often conjugated to a targeting moiety such as an antibody. 8,9 Among the metallic radionuclides employed for PET imaging, gallium-68 stands out as an attractive choice due to its convenient decay profile (mean β + energy of 0.89 MeV; t 1/2 = 68 min) and high positron yield (89%), which allow for sufficient levels of radioactivity for the production of highquality images while minimizing the exposure of patients to a prolonged large and damaging dose of radiation.…”

“… − Unfortunately, the high kinetic inertness of DOTA-based gallium complexes that advantageously slows dechelation and transmetalation to a time many-fold greater than the half-life of gallium-68 also imposes harsh reaction conditions for the formation of the complex. With such macrocyclic ligands, high temperatures, low pHs, and long reaction times (e.g., 90 °C, pH 3–5, and 30 min, respectively) are typically required to reach adequate radiolabeling yields. − Although such harsh conditions can be used with many peptide conjugates, they are incompatible with many targeting antibodies. Moreover, much of the radioactivity of gallium-68 decays during the long reaction times needed for DOTA complexation.…”

Arginine–Arginine–Leucine Peptide Targeting Heat Shock Protein 70 for Cancer Imaging

“…Furthermore, in recent years, it has been found that the RRL peptide can also bind to a variety of tumor cells, such as HepG2, HT-1080, and PC-3 cells . Based on these results, our team started to develop RRL peptides, particularly 99m Tc-labeled radiopharmaceuticals. − Tumor imaging and biodistribution demonstrated obvious 99m Tc-RRL uptake in the subcutaneous tumor models and pulmonary metastasis models . These findings implied that the RRL probe may present the valuable tumor accumulation performance, but the labeling yield needs to be improved.…”