Ga[NO2A-N-(alfa-amino)propionate] chelates: synthesis and evaluation as potential tracers for 68Ga3+ PET

The availability of commercial 68Ge/68Ga cyclotron-independent 68Ga3+ generators is making Positron Emission Tomography (PET) accessible to most hospitals, which is generating a surge of interest in the design and synthesis of bi-functional chelators for Ga3+. In this work we introduce the NO2A-N-(alfa-amino)propionic acid family of chelators based on the triazacyclononane scaffold. Complexation of the parent NO2A-N-(alfa-amino)propionic acid chelator and of a low molecular weight (model) amide conjugate with Ga3+ was studied by 1H and 71Ga NMR. The Ga3+ chelate of the amide conjugate shows pH-independent N3O3 coordination in the pH range 3-10 involving the carboxylate group of the pendant propionate arm in a 6 member chelate. For the Ga[NO2A-N-(alfa-amino)propionate] chelate, a reversible pH-triggered switch from Ga3+ coordination to the carboxylate group to coordination to the amine group of the propionate arm, was observed upon pH increase/decrease in the pH range 4-6. This phenomenon can conceivably constitute the basis of a physiological pH sensor. Both complexes are stable in the physiological range. The [67Ga][NO2A-N-(alfa-benzoylamido)propionate] chelate was found to be stable in human serum. Biodistribution studies of the 67Ga3+-labeled pyrene butyric acid conjugate NO2A-N-(alfa-pyrenebutanamido)propionic acid revealed that, despite its high lipophilicity and concentration-dependent aggregation properties, the chelate follows mainly renal elimination with very low liver/spleen accumulation and no activity deposition in bones after 24 hours. Facile synthesis of amide conjugates of the NO2A-N-(alfa-amino)propionic acid chelator, serum stability of the Ga3+chelates and fast renal elimination warrant further evaluation of this novel class of chelators for PET applications.This work was financially supported by Fundação para a Ciência e Tecnologia, Portugal: PEst-C/QUI/UI0686/2013; FCOMP-01-0124-FEDER-037302; PTDC/QUI/70063/2006; grant SFRH/BD/63994/2009 to Miguel Ferreira and sabbatical grant SFRH/BSAB/1328/2013 to J. A. Martins; Rede Nacional de RMN (REDE/1517/RMN/2005) for the acquisition of the Varian VNMRS 600 NMR spectrometer at the University of Coimbra and the Bruker Avance-3 400 Plus at the University of Minho in Braga. We also acknowledge the COST Action TD1004 “Theragnostics Imaging and Therapy”