N(epsilon) functionalization of metal and organic protected L-histidine for a highly efficient, direct labeling of biomolecules with [Tc(OH2)3(CO)3]+.
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.
Institute of Inorganic Chemistry, University of Zürich, Winterthurerstrasse 190, 8057 Zürich, Switzerland.
Jae Kyoung
JK
Pak
Paul
P
Benny
Bernhard
B
Spingler
Kirstin
K
Ortner
Roger
R
Alberto
D000477:Alkylating Agents / Q000737:chemistry; D018360:Crystallography, X-Ray; D006639:Histidine / Q000737:chemistry*; D006868:Hydrolysis; D007202:Indicators and Reagents; D007553:Isotope Labeling / Q000379:methods; D009682:Magnetic Resonance Spectroscopy; D008670:Metals / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D010084:Oxidation-Reduction; D019275:Radiopharmaceuticals / Q000138:chemical synthesis*; D017556:Technetium Compounds / Q000138:chemical synthesis*; D014508:Urea / Q000737:chemistry
D000477:Alkylating Agents; D007202:Indicators and Reagents; D008670:Metals; D019275:Radiopharmaceuticals; D017556:Technetium Compounds; D006639:Histidine; D014508:Urea