Versatile synthetic approach to new bifunctional chelating agents tailor made for labeling with the fac-[M(CO)(3)](+) core (M = Tc, (99m)Tc, Re): synthesis, in vitro, and in vivo behavior of the model complex [M(APPA)(CO)(3)] (APPA = [(5-amino-pentyl)-pyridin-2-yl-methyl-amino]-acetic acid).
A general synthetic approach for potent tridentate, bifunctional chelating agent (BFCA) for the [M(CO)(3)](+) fragment (M = (99g)Tc, (99m)Tc, and Re) has been elaborated. The strategy allows the facile preparation of BFCA with a pendent amino or carboxylic acid functionality for coupling to peptides and proteins via formation of an amide bond. [(5-amino-pentyl)-pyridin-2-yl-methyl-amino]-acetic acid (APPA) and [pyridin-2-yl-methyl-amino]-diacetic acid (PADA) were synthesized according to this protocol. The BFCA were labeled with the [M(CO)(3)](+) fragment, which resulted in formation of uniform products with a ligand to metal ratio of 1:1. The complexes have been fully characterized by means of mass spectrometry, IR, and NMR ((1)H, (13)C, (99)Tc) spectroscopy. Coordination of the tricarbonyl core with APPA and PADA was exclusively tridentate (via the acid function, the ternary amine, and the pyridine nitrogen). On the n.c.a. level the complexes were almost quantitatively formed (yield >90%) at ligand concentrations of 10+/-2 microM (PADA) or 50+/-4 microM (APPA) after 30 min at 70 degrees C. Chromatographic behavior of the (99m)Tc complexes is similar to that of the corresponding (99)Tc/Re complexes suggesting the identical chemical structure. Pharmacokinetic experiments with the (99m)Tc-APPA complex were performed in BALB/c mice and compared with previously published results of the (99m)Tc-PADA complex. The (99m)Tc-APPA complex revealed good clearance from the blood pool (0.29 +/- 0.03% ID after 24h p.i.) and a low uptake in the liver (2.41 +/- 0.14% ID/g), in the kidneys (2.81 +/- 0.12% ID/g) and other tissue and organs.
Stichelberger
Albert
A
Center for Radiopharmaceutical Science of the ETH Zürich, Paul Scherrer Institute Villigen and the University Hospital Zürich, CH-5232 Villigen, Switzerland.
Waibel
Robert
R
Dumas
Cécile
C
Schubiger
P A
PA
Schibli
Roger
R
D000818:Animals; D003432:Cross-Linking Reagents / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D004355:Drug Stability; D005260:Female; D007553:Isotope Labeling / Q000379:methods*; D008657:Metabolic Clearance Rate; D051379:Mice; D008807:Mice, Inbred BALB C; D009928:Organ Specificity; D015609:Organotechnetium Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics*; D011868:Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D012211:Rhenium / Q000737:chemistry / Q000493:pharmacokinetics; D014018:Tissue Distribution; D014915:Whole-Body Counting
D003432:Cross-Linking Reagents; D015609:Organotechnetium Compounds; D011868:Radioisotopes; D019275:Radiopharmaceuticals; C483761:technetium 99m tricarbonyl(((5-aminopentyl)pyridin-2-ylmethylamino)acetic acid); C483762:technetium 99m tricarbonyl((pyridin-2-ylmethylamino)diacetic acid); D012211:Rhenium