Several HER2-specific peptides are being continuously explored to find a candidate with suitable pharmacokinetic properties for development of effective radiopharmaceutical that can find applications for clinical screening of breast cancer patients. In the present work with an aim of preparing a radiopeptide with improved metabolic stability and in vivo pharmacokinetic performance we modified our previously reported [Lu]DOTA-L-A9 peptide. Here we designed an 'inverso' peptide with all d-amino acids and a 'retro-inverso' peptide where sequence of d-amino acids was reversed. Higher secondary structure stabilization of retro- inverso A9 variant compared to inverso A9 peptide was evident by circular dichroism studies. The two radiopeptides [Lu]DOTA-D-A9 and [Lu]DOTA-rD-A9 exhibited significantly improved in vivo metabolic stability over the original l-peptide. The retro-inverso variant, [Lu]DOTA-rD-A9 demonstrated better pharmacokinetic behavior with significantly higher tumor uptake than the inverso peptide, [Lu]DOTA-D-A9 and the original peptide, [Lu]DOTA-L-A9. In the present case of A9 peptide, reversal of the peptide sequence of d-amino acids boosted the uptake and retention of radioactivity in HER2-positive tumor. The present study can thus guide the design and development of newer and improved versions of peptides.
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| http://dx.doi.org/10.1016/j.bioorg.2023.106761 | DOI Listing |
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