Ga[NO2A-N-(α-amino)propionate] chelates: synthesis and evaluation as potential tracers for ⁶⁸Ga PET.
The availability of commercial (68)Ge/(68)Ga cyclotron-independent (68)Ga(3+) 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 Ga(3+). In this work we introduce the NO2A-N-(α-amino)propionic acid family of chelators based on the triazacyclononane scaffold. Complexation of the parent NO2A-N-(α-amino)propionic acid chelator and of a low molecular weight (model) amide conjugate with Ga(3+) was studied by (1)H and (71)Ga NMR. The Ga(3+) 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-(α-amino)propionate] chelate, a reversible pH-triggered switch from Ga(3+) 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 [(67)Ga][NO2A-N-(α-benzoylamido)propionate] chelate was found to be stable in human serum. Biodistribution studies of the (67)Ga(3+)-labeled pyrene butyric acid conjugate NO2A-N-(α-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-(α-amino)propionic acid chelator, serum stability of the Ga(3+) chelates and fast renal elimination warrant further evaluation of this novel class of chelators for PET applications.
Centro de Química (CQ-UM), Universidade do Minho, Campus de Gualtar, 4710-057 Braga, Portugal. jmartins@quimica.uminho.pt.
Miguel F
MF
Ferreira
Goretti
G
Pereira
João P
JP
André
M I M
MI
Prata
Paula M T
PM
Ferreira
José A
JA
Martins
Carlos F G C
CF
Geraldes
D000577:Amides / Q000737:chemistry*; D000818:Animals; D002614:Chelating Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D005708:Gallium / Q000737:chemistry* / Q000493:pharmacokinetics; D005710:Gallium Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D049268:Positron-Emission Tomography / Q000379:methods*; D011422:Propionates / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D017208:Rats, Wistar
D000577:Amides; D002614:Chelating Agents; D005710:Gallium Radioisotopes; D011422:Propionates; D005708:Gallium; C029658:propionic acid