Improved Pharmacokinetics Following PEGylation and Dimerization of a c(RGD-ACH-K) Conjugate Used for Tumor Positron Emission Tomography Imaging

Abstract

Improving the in vivo pharmacokinetics (PK) of positron emission tomography (PET) radiotracers is of critical importance to tumor diagnosis and therapy. In the case of peptide-based radiotracers, the modification and addition of a linker or spacer functional group often offer faster in vivo pharmacokinetic behavior. In this study, the authors introduced two new PEGlyated dimeric c(RGD-ACH-K) conjugates, in which an aminocyclohexane carboxylic acid (ACH) is inserted into the ring chain of the cyclic RGD peptides, with a common bifunctional chelator (DOTA or NOTA) used for labeling with radiometals (including ⁶⁸Ga and ⁶⁴Cu). The addition of polyethylene glycol (PEG) and dimerization of c(RGD-ACH-K) affected the PK of the renal system and the tumor-targeting ability, relative to unmodified molecule. As a result, both ⁶⁴Cu-DOTA-E[c(RGD-ACH-K)]₂ (complex 1) and ⁶⁴Cu-NOTA-E[c(RGD-ACH-K)]₂ (complex 2) exhibited specific tumor-targeting properties relative to tumor-blocking control group, most likely resulting from improved in vivo tumor imaging. The in vivo tumor-to-blood ratio of the ⁶⁴Cu(NOTA) complex shows better PET imaging than that of the ⁶⁴Cu(DOTA) complex, which should lead to improved dosimetry and increased suitability for noninvasive monitoring of tumor growth or tumor-targeted radionuclide therapy.