[64Cu]Cu-CryptTM – A novel cryptate for copper-64?

Methods: Stability of [64Cu]Cu-CryptTM was assessed in vitro by challenging experiments using competitive chelators EDTA and NOTA. Radiopharmacological profile of [64Cu]Cu-CryptTM was evaluated by dynamic PET studies in EMT6-tumor bearing Balb/C mice. The current “gold standard” for kinetically inert 64Cu-cryptates [64Cu]Cu-DiAmSar was prepared and used as internal reference for in vitro and in vivo studies. Results: Radiochemical yields of > 95% were achieved by mixing CryptTM (0.25 nmol/μL) and [64Cu]Cu(OAc)2 (4.1 ± 0.5 MBq/μL) for 60 min at 37 °C. EDTA and NOTA clearly demonstrated kinetically- and thermodynamically-driven trans-chelation. Dynamic PET studies showed fast blood clearance for [64Cu]Cu-CryptTM and [64Cu]Cu-DiAmSar. [64Cu]Cu-CryptTM was predominantly eliminated hepatobiliary. Uptake of [64Cu]Cu-CryptTM in EMT6 tumors resulted in an SUV 0.40 ± 0.03 which was higher compared to muscle (SUV 0.16 ± 0.02 (n = 3) 60 min p.i.). Conclusion: Radiopharmacological evaluation of [64Cu]Cu-CryptTM revealed insufficient kinetic stability for in vivo applications. However, the facile synthetic access and its favorable 64Cu-labeling properties warrant further investigation of related derivatives possessing a tri-pyridyl/tri-amine donor group set to allow the formation of more kinetically inert 64Cu-cryptates