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Potential Gallium-68 Tracers for Imaging the Heart with PET: Evaluation of Four Gallium Complexes with Functionalized Tripodal Tris(Salicylaldimine) Ligands

Departments of Medicinal Chemistry and Chemistry, Purdue University, West Lafayette, Indiana
Mallinckrodt Medical, Inc., St. Louis, Missouri

Correspondence: For correspondence or reprints contact: Mark A. Green, PhD, Department of Medicinal Chemistry, Pharmacy Building, Purdue University, West Lafayette, IN 47907.

ABSTRACT

Gallium-67 and ^68>Ga complexes have been synthesized with tripodal hexadentate salicylaldimine ligands derived from 1.1,1-tris(salicylaldiminomethyl)ethane, sal₃tame. The four ligands evaluated contained alkoxy substituents (n-BuO-, iso-BuO-, sec-BuO-, and n-PrO-) on the terminal ethane carbon of the ligand backbone. In the case of the n-PrO-derivative, the tris(salicylaldimine) ligand was additionally substituted with methoxy groups in the 5-position of the aromatic rings. The ⁶⁷Ga and ⁶⁸Ga-complexes of these ligands were prepared by ligand exchange from ⁶⁷Ga-or ⁶⁸Ga-acetylacetonate in ethanol. The nonradioactive Ga[(sal)₃tame-O-iso-Bu] complex was similarly prepared and shown by x-ray crystallography to exhibit the expected pseudo-octahedral N₃O₃^3- coordination sphere about the Ga³⁺ center. These Ga-radiotracers are highly lipophilic, as demonstrated by their octanol/water partition coefficients. Log P values of 3.1, 3.1, 2.6, and 2.5 were found for the [(sal)₃tame-O-iso-Bu},[(sal)₃tame-O-n-Bu], [(sal)₃tame-O-sec-Bu], and [(5-MeOsal)₃tame-O-n-Pr] complexes, respectively. Following intravenous injection into rats, these complexes are rapidly cleared from the blood and exhibit significant myocardial uptake. At 1 min postinjection, 2.4%, 2.0%, 2.1% and 1.1% of the injected dose was found in the heart for the iso-BuO, n-BuO, sec-BuO, and n-PrO complexes, respectively, dropping to 1.0%, 0.8%, 0.8%, and 0.7% at 5 min. The corresponding heart-to-blood ratios are quite high: 17 ± 3, 14 ± 2, 12 ± 2 and 3.5 ± 0.4 at 1 min and 14 ± 4, 10 ± 1, 10 ± 1 and 3.2 ± 0.1 at 5 min postinjection. High quality myocardial images were obtained with PET in a normal dog using data collected from 2 to 10 min following intravenous injection of ⁶⁸Ga[(sal)₃tame-O-iso-Bu].

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