title: Evaluation of gallium-68 tris(2-mercaptobenzyl)amine: a complex with brain and myocardial uptake.
abstract: Previous research into development of a gallium-radiolabeled agent that crosses the blood-brain barrier has met with limited success. In this study, we focused our attention on a Ga(III) complex of a 4-coordinate amine trithiolate tripod ligand, tris(2-mercaptobenzyl) amine (S3N). The Ga(III) S3N complex is small, neutral, and lipophilic, meeting the requirements for a potential brain imaging agent. The Ga-68 complex was easily formed with a radiochemical purity of >95%. In vitro stability of the Ga-S3N complex, determined in rat serum incubated at 37 degrees C, was greater than 95% intact at 2 h by silica gel and reversed-phase radio-thin layer chromatography. Biodistribution studies conducted in female Sprague-Dawley rats showed the complex cleared rapidly from the blood with initial high liver uptake followed by rapid washout. Significant uptake was observed in the brain, with brain:blood ratios increasing from 0.11 at 2 min postinjection to 3.8 at 60 min postinjection. Uptake was also observed in the heart going from a heart:blood ratio of 2.3 at 2 min postinjection to 11 at 60 min postinjection. Molecular mechanics were used to determine the coordination number, and demonstrated that the Ga(III) complex prefers to be 4-coordinate. Imaging studies with 68Ga-S3N in a Nemestrina macaque showed significant brain uptake, similar to other lipophilic agents. The extraction of 68Ga-S3N into the brains of both rodents and primates, higher than any 68Ga agent reported in the literature, suggests that this compound may have potential as a brain imaging agent for positron emission tomography.
authors.affiliation: The Edward Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: C S
authors.initials: CS
authors.lastname: Cutler
authors.forename: M C
authors.initials: MC
authors.lastname: Giron
authors.forename: D E
authors.initials: DE
authors.lastname: Reichert
authors.forename: A Z
authors.initials: AZ
authors.lastname: Snyder
authors.forename: P
authors.initials: P
authors.lastname: Herrero
authors.forename: C J
authors.initials: CJ
authors.lastname: Anderson
authors.forename: D A
authors.initials: DA
authors.lastname: Quarless
authors.forename: S A
authors.initials: SA
authors.lastname: Koch
authors.forename: M J
authors.initials: MJ
authors.lastname: Welch
mesh_terms: D000818:Animals; D001345:Autoradiography; D001812:Blood-Brain Barrier / Q000502:physiology; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D002250:Carbon Radioisotopes; D006224:Cricetinae; D004285:Dogs; D004355:Drug Stability; D000431:Ethanol / Q000493:pharmacokinetics; D005260:Female; D005710:Gallium Radioisotopes / Q000737:chemistry; D006321:Heart / Q000000981:diagnostic imaging*; D008168:Lung / Q000000981:diagnostic imaging / Q000378:metabolism; D008254:Macaca nemestrina; D008297:Male; D008647:Mesocricetus; D009206:Myocardium / Q000378:metabolism*; D009942:Organometallic Compounds / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D019275:Radiopharmaceuticals / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013882:Thiosemicarbazones / Q000493:pharmacokinetics; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed
chemical_list: D002250:Carbon Radioisotopes; D005710:Gallium Radioisotopes; D009942:Organometallic Compounds; D019275:Radiopharmaceuticals; D013882:Thiosemicarbazones; C120245:gallium tris(2-mercaptobenzyl)amine; C052629:copper pyruvaldehyde bis(N(4)-methylthiosemicarbazone) complex; D000431:Ethanol