N^ε Functionalization of Metal and Organic Protected L‐Histidine for a Highly Efficient, Direct Labeling of Biomolecules with [Tc(OH₂)₃(CO)₃]⁺

Abstract

Two different pathways for the introduction of an acetyl group at N(epsilon ) in a N(alpha), N(delta), and -COO protected histidine to afford N(epsilon)-(CH(2)COOH)-histidine derivative 7 b are presented. The purpose of this study is the coupling of 7 b to amino groups in bioactive molecules such as peptides. After full deprotection of such a bioconjugate, histidine provides three coordination sites which efficiently coordinate to [(99m)Tc(OH(2))(3)(CO)(3)](+) or [Re(OH(2))(3)(CO)(3)](+) in a facial geometry. This allows the development of novel radiopharmaceuticals. Selective derivatization at the N(epsilon) position has conveniently been achieved by concomitant protection of N(alpha) and N(delta) with a carbonyl group forming a six-membered urea. Cyclic urea ring opening with Fm-OH, coupling of phenylalanine as a model to 7 b through its primary amine and removing of all protecting groups in one step gave a histidine derivative of phenylalanine which could be labeled at 10(-5) M with (99m)Tc in very high yield and even in about 50 % yield at 10(-6) M. The Xray structure of a complex with [Re(CO)(3)](+) in which anilin is coupled to 7 b confirms the facial arrangement of histidine. A second pathway applies directly the [Re(CO)(3)](+) moiety as a protecting group. This is one of the rare examples in which a metal fragment is used as a protecting group for organic functionalities. The coordination to histidine protects the N(alpha), N(delta) and COO group in one single step, subsequent alkylation with BrCH(2)COOH(R) at N(epsilon), coupling to phenylalanine and oxidative deprotection of [Re(CO)(3)](+) to [ReO(4)](-) gave the corresponding bioconjugate in which histidine is coupled to phenylalanine through an acetylamide at N(epsilon). Both methods offer convenient pathways to introduce histidine in a biomolecule under retention of its three coordination sites. The procedures are adaptable to any biomolecule with pendant amines and allow the development of novel radiopharmaceuticals or inversed peptides.

Functionalised Tris(pyrazolyl)methane Ligands and Re(CO)3 Complexes Thereof

“…[1][2][3] Several groups are developing ligands for the radio-labelling of bio-molecules. [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] Many of these ligating moieties are based upon bis(pyridylmethyl)amine derivatives and we have also developed a N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer with bis(pyridylmethyl)amine derivatives as metal binding sites. [19] Another class of widely used ligands in coordination chemistry and organometallic chemistry are the tris(pyrazolyl)borates (Tp), developed by Trofimenko in the early sixties.…”

Synthesis and Evaluation of Bombesin Analogues Conjugated to Two Different Triazolyl‐Derived Chelators for 99mTc Labeling

“…[35,36] The resulting triazole ring is known to be a good ligand for various transition metals. [37] We evaluated the synthesis of these triazole-based chelators and their capacity for labeling with the 99m Tc(CO) 3 core.…”

Mono‐, bi‐, or tridentate ligands? The labeling of peptides with 99mTc‐carbonyls

“…The crucial step is the formation of a six-membered urea ring in histidine that protects ␣-N and ␦-N in one single step. 24 Sub- sequently, ⑀-N can be alkylated with organic halides that bear the coupling group of choice. A rather reactive cation is formed in which the urea ring can conveniently be opened with an alcohol such as fluorenol to yield directly the 9-flourenylmethyoxycarbonyl (Fmoc)-protected ␣-N.…”