Theoretical studies on substitution isomerism and tautomerism in iodo-histamine molecules P. Garnuszek a, * , J.Cz. Dobrowolski a,b , A.P. Mazurek a a Drug Institute, 30/34 Cheømska Street, 00-725 Warsaw, Poland b Industrial Chemistry Research Institute, 8 Rydygiera Street, 01-793 Warsaw, Poland Received 18 January 1999; received in revised form 7 September 1999; accepted 30 September 1999 Abstract Stabilization energies DE (kcal/mol) of various substitution isomers of the two tautomeric iodo-histamine forms have been calculated at the RHF/3-21G pp , MP2/3-21G pp and HF/Sadlej-PTZ levels. The most stable forms are produced by iodo-substitu- tion of histamine in the side chain, ca. 95% of the 5-(2 0 -amino-2 0 -iodoethyl)-3H-imidazole and ca. 5% of the 5-(2 0 -amino-2 0 - iodoethyl)-1H-imidazole isomer. If iodo-substituted is the imidazole ring only, then the 4-iodo-histamine and 2-iodo-histamine N(1)-H tautomers are predicted to coexist is a mole ratio of ca. 95:5. The only stable form of the deprotonated histamine anion is that with both the imidazole nitrogen atoms deprotonated. q 2000 Elsevier Science B.V. All rights reserved. Keywords: Ab initio; Iodo-histamine; Substitution isomerism; Tautomerism 1. Introduction The iodo derivatives of histamine (Scheme 1) which contain 125 I radioisotope, have been used for many years as isotope-carriers in RIA systems. Many steroid hormones [1±4] or some drugs like cyclosporine [5] have been successfully labeled by conjugation to 125 I-iodo-histamine, and routinely used for in vitro diagnostic tests. Recently, there has been observed an increasing interest for in vivo application (diagnostic or radiotherapeutic) of some radiopharmaceuticals prepared by coupling with radio-iodinated histamine [6±9]. Although the iodo derivatives of histamine have proved to be inactive toward histamine receptors [10], so far nobody has tried to explain the reasons. In vitro biological studies have shown polar substituents in the histamine imidazole ring to suppress the histaminic activities [11]. Substitution of a large iodine atom in the small histamine molecule should evidently affect the parent molecule by imparting a complete passiveness toward histamine receptors. The 4-I-histamine (5-(2 0 -aminoethyl)-imidazole-4- iodo) is the most stable form of the iodo-histamine derivatives substituted in the imidazole ring [12]. However, so far no explanation has been reported on the in¯uence of the iodine atom substitution on the histamine structure and tautomerism. The growing interest for the use of iodo-histamine for preparing in vivo applicable radiopharmaceuticals [7±9,13], needs investigations on the iodo-histamine structure and the substituent in¯uence on the structure stability and behavior in biological systems to be undertaken. This paper sets out to present part of the study concerned with the isomerism of monoiodo-hista- mine. Quantum chemical methods have been applied to provide a deeper understanding of the role of iodine Journal of Molecular Structure (Theochem) 507 (2000) 145±151 0166-1280/00/$ - see front matter q 2000 Elsevier Science B.V. All rights reserved. PII: S0166-1280(99)00372-3 www.elsevier.nl/locate/theochem * Corresponding author. Fax: 10048-22-41-06-52. E-mail address: pg@il.waw.pl (P. Garnuszek).