title: Evaluation of bifunctional chelates for the development of gallium-based radiopharmaceuticals.
abstract: Ga radioisotopes, including the generator-produced positron-emitting isotope (68)Ga (t1/2 = 68 min), are of increasing interest for the development of new radiopharmaceuticals. Bifunctional chelates (BFCs) that can be efficiently radiolabeled with Ga to yield complexes with good in vivo stability are needed. To this end, we undertook a systematic comparison of four BFCs containing different chelating moieties: two novel BFCs, p-NO2-Bn-Oxo (1-oxa-4,7,10-triazacyclododecane-4,7,10-triacetic acid) and p-NO2-Bn-PCTA (3,6,9,15-tetraazabicyclo [9.3.1]pentadeca-1(15),11,13-triene-3,6,9-triacetic acid), and two more commonly used BFCs, p-NO2-Bn-DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) and p-NO2-Bn-NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid). Each BFC was compared with respect to radiolabeling conditions, radiochemical yield, stability, and in vivo clearance properties. p-NO2-Bn-PCTA, p-NO2-Bn-Oxo, and p-NO2-Bn-NOTA were all more efficiently radiolabeled with Ga compared to p-NO2-Bn-DOTA. p-NO2-Bn-DOTA required longer reaction time, higher concentrations of BFC, or heating to obtain equivalent radiochemical yields. Better stability was observed for p-NO2-Bn-NOTA and p-NO2-Bn-PCTA compared to p-NO2-Bn-DOTA and p-NO2-Bn-Oxo, especially with respect to transmetalation to transferrin. Ga-radiolabled p-NO2-Bn-Oxo was found to be kinetically labile and therefore unstable in vivo. Ga-radiolabeled p-NO2-Bn-NOTA and p-NO2-Bn-PCTA were relatively inert, while Ga-radiolabeled p-NO2-Bn-DOTA had intermediate stability, losing >20% of Ga in less than one hour when incubated with apo-transferrin. Similar stability differences were seen when incubating at pH 2. In vivo PET imaging and biodistribution studies in mice showed that (68)Ga-radiolabeled p-NO2-Bn-PCTA, p-NO2-Bn-NOTA, and p-NO2-Bn-DOTA all cleared through the kidneys. While there was no statistical difference in the biodistribution results of (68)Ga-radiolabeled p-NO2-Bn-PCTA and p-NO2-Bn-DOTA, (68)Ga-radiolabeled p-NO2-Bn-NOTA cleared more rapidly from blood and muscle tissue but retained at up to 5 times higher activity in the kidneys.
authors.affiliation: MDS Nordion, 4004 Wesbrook Mall, Vancouver, British Columbia, Canada V6T 2A3, Ottawa Heart Institute, Ottawa, Ontario, Canada, MDS Nordion, Kanata, Ontario, Canada, and Macrocyclics, Dallas, Texas.
authors.forename: Cara L
authors.initials: CL
authors.lastname: Ferreira
authors.forename: Eric
authors.initials: E
authors.lastname: Lamsa
authors.forename: Michael
authors.initials: M
authors.lastname: Woods
authors.forename: Yin
authors.initials: Y
authors.lastname: Duan
authors.forename: Pasan
authors.initials: P
authors.lastname: Fernando
authors.forename: Corinne
authors.initials: C
authors.lastname: Bensimon
authors.forename: Myra
authors.initials: M
authors.lastname: Kordos
authors.forename: Katharina
authors.initials: K
authors.lastname: Guenther
authors.forename: Paul
authors.initials: P
authors.lastname: Jurek
authors.forename: Garry E
authors.initials: GE
authors.lastname: Kiefer
mesh_terms: D000818:Animals; D002614:Chelating Agents / Q000737:chemistry* / Q000493:pharmacokinetics; D005710:Gallium Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics; D007700:Kinetics; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D014018:Tissue Distribution
chemical_list: D002614:Chelating Agents; D005710:Gallium Radioisotopes; D009942:Organometallic Compounds; D019275:Radiopharmaceuticals