Chemical biology & drug design

Synthesis and comparative in vivo evaluation of (99m) Tc(CO)3 -labeled PEGylated and non-PEGylated cRGDfK peptide monomers.

PMID 27561428


This work aimed at studying the effect of insertion of medium PEG (PEG7 ) on the pharmacokinetic behavior of cRGDfK peptide in comparison with the non-PEGylated analogue. The cRGDfK peptide has thus been derivatized at ε-amino group of lysine by conjugation with N3 -PEG7 -COOH/N3 -CH2 -COOH to prepare a PEGylated and a non-PEGylated analogue of cRGDfK. A tridentate chelator was then incorporated by click chemistry conjugation of the two peptide azides for radiolabeling with [(99m) Tc(CO)3 (H2 O)3 ](+) precursor. Comparative in vivo evaluation of the two (99m) Tc(CO)3 -labeled radiotracers, (99m) Tc(CO)3 -Pra-Tz-CH2 -cRGDfK 5 and (99m) Tc(CO)3 -Pra-Tz-PEG7 -cRGDfK 6, was carried out in C57BL/6 mice bearing αv β3 -positive melanoma tumors to determine their potential toward targeting integrin αv β3 receptors. The radiotracers exhibited excellent stability in saline as well as in serum. Maximum tumor uptake for the two radiotracers was observed at 30xa0min p.i. (5: 3.0xa0±xa00.7% ID/g; 6: 4.1xa0±xa00.5% ID/g). The two neutral (99m) Tc(CO)3 radiotracers prepared exhibited receptor-mediated uptake in melanoma tumor. The increase in the tumor uptake on introduction of PEG7 unit was accompanied by slower clearance from other organs which resulted in decreased target-to-background ratios. The in vivo kinetics of (99m) Tc(CO)3 -labeled radiotracer, (99m) Tc(CO)3 -Pra-Tz-CH2 -cRGDfK 5 with only methylene unit as the spacer, was found to be more favorable due to higher tumor/blood, tumor/liver, tumor/kidney, and tumor/lung ratios.

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2-Azidoacetic acid, 97%