Mixed ligand fac-tricarbonyl complexes of the general formula [M(L1)(L2)(CO)3](M = Re, 99(m)Tc, L1= imidazole, benzyl isocyanide, L2 = 1H-imidazole-4-carboxylic acid, pyridine-2,4-dicarboxylic acid, pyridine-2,5-dicarboxylic acid) have been prepared starting from the precursors [M(OH2)3(CO)3]+. The complexes can be obtained in good yield and purity in a two-step procedure by first attaching the bidentate ligand followed by addition of the monodentate. 99mTc compounds can also be prepared at the tracer level in one-pot procedures with L1 and L2 being concomitantly present. This [2 + 1] approach allows the labeling of bioactive molecules containing a monodentate or a bidentate donor site. Examples given in here are N-(tert-butoxycarbonyl)glycyl-N-(3-(imidazol-1-yl)propyl)phenylalaninamide, 5-((3-(imidazol-1-yl)propyl)aminomethyl)-2'-deoxyuridine and 4-(5-isonitrilpentyl)-1-(2-methoxyphenyl)-piperazine as L1 and N-((6-carboxypyridine-3-yl)methyl)glycylphenylalanine as L2. The corresponding second ligand can be used to influence the physico-chemical properties of the conjugate. The crystal structures of [99Tc(OH2)(imc)(CO)3], [Re(OH2)(2,4-dipic)(CO)3], [Re(bic)(2,4-dipic)(CO)3] and [Re(im)(2,5-dipic)(CO)3] are reported.
Rapidly growing cells show an increased demand for nutrients and vitamins. The objective of our work is to exploit the supply route of vitamin B12 to deliver new derivatives of this vital vitamin to hyperproliferative cells. To date, radiolabeled ( 57 Co and 111 In) vitamin B12 derivatives showed labeling of tumor tissue but also undesired high accumulation of radioactivity in normal tissue. By abolishing the interaction of a tailored vitamin B12 derivative to its transport protein transcobalamin II and therefore interrupting transcobalamin II receptor and megalin mediated uptake in normal tissue, preferential accumulation of a radiolabeled vitamin in cancer tissue could be accomplished. We identified transcobalamin I on tumors as a possible new receptor for this preferential accumulation of vitamin-mediated targeting. The low systemic distribution of radioactivity and the high tumor to blood ratio opens the possibility of a more successful clinical application of vitamin B12 for imaging or therapy.
cis-[PtCl(OH2)(NH3)2]+, the monoactivated form of cisplatin, reacts with the cyano ligand of cobalt in vitamin B12 (cyanocobalamin) to form a Co-C[triple chemical bond]N-Pt conjugate (1). Compound 1 is prepared in good yield directly in aqueous solution. The remaining chloride ligand of Pt(II) is labile. It hydrolyzes slowly in aqueous solution and can be exchanged by stronger coordinating ligands, such as 9-methylguanine or 2'-deoxyguanosine, to yield vitamin B12-nucleobase conjugates. X-ray structures of the vitamin B12-cisplatin conjugate 1 as well as of the product with coordinated 9-methylguanine (2) are presented. The coordination geometry at Pt(II) is almost perfectly square-planar. The structure of the cobalamin compound remains essentially unchanged when compared with the original B(12) structure. The guanine moiety of compound 2 binds in a 45 degrees angle to the cisplatin molecule and interacts with neighboring molecules by means of pi stacking and hydrogen bonds.
The labeling of targeting peptides with (99m)Tc is a useful concept for the diagnosis of various diseases such as cancer. Although in research for at least one decade, only a very few radiopharmaceuticals based on peptides are in clinical use. The difficulty of labeling, and the resulting authenticity of the new vector, is largely responsible for this observation. In this overview, we present an alternate strategy based on the organometallic fac-[(99m)Tc(CO)(3)](+) core for introducing (99m)Tc in biomolecules in general and in peptides in particular. The three coordination sites available in [(99m)Tc(OH(2))(3)(CO)(3)](+) can be occupied with many different ligand types, pendant to a biomolecule and serving as the anchor group for labeling. This makes the appropriate choice difficult. We intend to present some useful concepts for the practice. Monodentate chelators are robust but bear the risk of multiple binding of biomolecules. Coordinating a bidentate ligand of choice prior to labeling bypasses this problem and enables a systematic drug discovery by variation of the bidentate ligand. Bidentate ligands attached to the biomolecule are stronger but occasionally require protection of the remaining site by a monodentate ligand. Both approaches refer to a mixed-ligand [2+1] approach. Tridentate chelators are the most efficient but need some protecting group chemistry in order to achieve selectivity for the coupling process. Examples with cysteine and histidine are presented. This article aims to provide versatile and reproducible approaches for the labeling of biomolecules while not focusing on particular systems. It should be left to the readers to derive a strategy for their own peptide.
The preparation of new tricarbonyl(cyclopentadienyl)rhenium and tricarbonyl(cyclopentadienyl)technetium derivatives is described. The approach used was applied to a cold target model, 17α-ethynylestradiol substituted at the 17α position by a ketotricarbonyl(cyclopentadienyl)rhenium group. The novel organometallic reaction applied here, when extended to potential radiopharmaceuticals, consists of a cyclopentadienyl-ligand transfer between ketoferrocenes and fac-
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