title: Be spoilt for choice with radiolabelled RGD peptides: preclinical evaluation of ⁶⁸Ga-TRAP(RGD)₃.
abstract: Gallium-68 is rapidly gaining importance, as this generator-produced PET isotope is available independent of on-site cyclotrons, enabling radiopharmaceutical production with comparably simple techniques at low cost. The recently introduced TRAP chelator combines the advantage of straightforward design of multimeric ⁶⁸Ga-radiopharmaceuticals with very fast and efficient ⁶⁸Ga-labeling. We synthesized a series of five cyclo(RGDfK) peptide trimers and determined their α(v)β₃ integrin affinities in competition assays on α(v)β₃-expressing M21 human melanoma cells against ¹²⁵I-echistatin. The compound with highest IC₅₀, Ga-TRAP(RGD)₃, showed more than 7-fold higher affinity compared to the monomers F-Galacto-RGD and Ga-NODAGA-c(RGDyK). TRAP(RGD)₃ was radiolabeled with ⁶⁸Ga in a fully automated GMP compliant manner. CD-1 athymic nude mice bearing M21/M21L human melanoma xenografts were used for biodistribution studies, blockade experiments, metabolite studies and PET imaging. ⁶⁸Ga-TRAP(RGD)₃ exhibited high M21 tumor uptake (6.08±0.63% ID/g, 60 min p.i.), was found to be fully stable in vivo, and showed a fast renal clearance. Blockade studies showed that uptake in the tumor, as well as in all other tissues, is highly integrin specific. A comparison of biodistribution and PET data of ⁶⁸Ga-TRAP(RGD)₃ with those of ⁶⁸Ga-NODAGA-c(RGDyK) and ¹⁸F-Galacto-RGD showed that the higher affinity of the trimer effects a larger dynamic response of tracer uptake to integrin expression, i.e., enhanced integrin-specific uptake in all tissues. We conclude that ⁶⁸Ga-TRAP(RGD)₃ could allow for imaging of low-level integrin expression in tissues which are not visible with the two competitors. Overall, the study constitutes proof of concept for the favourable in vivo properties of TRAP-based ⁶⁸Ga radiopharmaceuticals.
authors.affiliation: Pharmaceutical Radiochemistry, Technische Universität München, Walther-Meißner-Str. 3, D-85748 Garching, Germany. johannes.notni@tum.de
authors.forename: Johannes
authors.initials: J
authors.lastname: Notni
authors.forename: Karolin
authors.initials: K
authors.lastname: Pohle
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Wester
mesh_terms: D000818:Animals; D056831:Coordination Complexes / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics; D004355:Drug Stability; D005260:Female; D005710:Gallium Radioisotopes; D006801:Humans; D016023:Integrins / Q000378:metabolism; D007553:Isotope Labeling; D008545:Melanoma / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009842:Oligopeptides / Q000737:chemistry*; D009943:Organophosphorus Compounds / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics; D010456:Peptides, Cyclic / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography
chemical_list: C581138:68Ga-TRAP(RGD)3; D056831:Coordination Complexes; D005710:Gallium Radioisotopes; D016023:Integrins; D009842:Oligopeptides; D009943:Organophosphorus Compounds; D010456:Peptides, Cyclic; C047981:arginyl-glycyl-aspartic acid