Impact of PKM Linkers on Biodistribution Characteristics of the ^99mTc-Labeled Cyclic RGDfK Dimer

Abstract

This report describes synthesis of three new cyclic RGDfK peptide conjugates, HYNIC-PKM-SU016 (PKM = E, K and PEG4), and in vivo evaluation of the impact of PKM linkers on biodistribution characteristics of their ternary ligand complexes [ 99m Tc(HYNIC-PKM-SU016)(tricine)(TPPTS)] in athymic nude mice bearing the MDA-MB-435 human breast cancer xenografts. Results from biodistribution studies show that PKM linkers have minimal impact on the integrin α v β 3 binding capability of radiotracers. Even though they have different charges under physiological conditions, all three linkers (E, K and PEG4) are able to reduce the uptake of 99m Tc-labeled E[c(RGDfK)] 2 in blood, kidneys, liver and lungs, and increase target-to-background (T/B) ratios at >30 min postinjection. E and K may have advantages over PEG4 due to a combination of relatively low liver uptake, high tumor/liver and tumor/lung ratios of ternary ligand complexes [ 99m Tc(HYNIC-PKM-SU016)(tricine)(TPPTS)] (PKM = E and K).

Evaluation of 99mTc-HYNIC-TMTP1 as a tumor-homing imaging agent targeting metastasis with SPECT

“…In the last several years, a variety of pharmacokinetic modifying (PKM) linkers have been used to improve the excretion kinetics of radiolabeled cyclic peptides. In this study, glutamic acid (E) was chosen as a PKM linker [27].…”

Linker Effects on Biological Properties of 111In-Labeled DTPA Conjugates of a Cyclic RGDfK Dimer

“…111 InCl 3 was obtained from Perkin-Elmer Life and Analytical Sciences (North Billarica, MA). E[c(RGDfK)] 2 and E-E[c(RGDfK)] 2 were prepared according to the procedure described in our previous communications (21,23). The reversed-phase C-18 SepPak cartridges were obtained from Waters (Milford, MA).…”

Development of a 99mTc-labeled lactam bridge-cyclized alpha-MSH derivative peptide as a possible single photon imaging agent for melanoma tumors

“…Different amino acids and hydrocarbon linkers displayed profound favorable effects on the receptor-binding affinities and pharmacokinetics of radiolabeled RGD [26], a-MSH peptides [18,20,27], and bombesin [28]. Miao et al [18] reported that introduction of a negatively charged linker (Gly-Glu) between the DOTA and CycMSH peptide sequence decreased the renal uptake by 44 % without affecting the tumor uptake at 4 h post injection.…”