Synthesis and Evaluation of Radiogallium Labeled Bone-Imaging Probes Using Oligo--Carboxy Glutamic Acid Peptides as Carriers to Bone

We investigated the importance of the carboxy group density in bone affinity during the development of peptide-based bone-seeking radiopharmaceuticals and carriers. Oligo-gamma-carboxy glutamic acid peptides [(Gla)(n)] with higher carboxy group density than oligo-glutamic acid peptides [(Glu)(n)] and oligo-aspartic acid peptides [(Asp)(n)] were chosen. Using the radiogallium chelator N,N '-bis-[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N '-diacetic acid (HBED-CC), we synthesized [Ga-67]Ga-HBED-CC-(Gla)(n) (n = 1, 2, 5, 8, 11, or 14) with high yields. Hydroxyapatite-binding assays, biodistribution, and SPECT imaging showed higher affinity and bone accumulation for [Ga-67]Ga-HBED-CC-(Gla)(n) compared to [Ga-67]Ga-HBED-CC-(Glu)(n). Notably, [Ga-67]Ga-HBED-CC-(Gla)(8) and [Ga-67]Ga-HBED-CC-(Gla)(11) exhibited superior bone accumulation and rapid blood clearance. SPECT/CT imaging with [Ga-67]Ga-HBED-CC-(Gla)(8) exclusively visualized the bone tissue. These findings support the potential use of [Ga-67]Ga-HBED-CC-(Gla)(n) as excellent bone-imaging PET probes, suggesting (Gla)(n) peptides are superior bone-seeking carriers.