[18F] fluoride cryptate complexes for radiolabeling fluorinations

Abstract

The present invention claims UV detectable (>210 nm) potassium [.sup.18F]fluoride diaryl- and aryl-fused [2.2.2]cryptate complexes suitable for performing radio-labeling reactions to generate [.sup.18F] fluorinated species.

Claims

1. A cryptate complex comprising potassium [.sup.18F] fluoride and an aryl-fused [2.2.2] cryptate wherein the cryptate is ##STR00003##

Description

DETAILED DESCRIPTION OF THE INVENTION

(1) The effect of substituents on macrocyclic molecules was first observed by Pedersen (Pedersen, C. J. J. Am. Chem. Soc. 1967, 89, 7017). Subsequently, many different moieties have been introduced into the macrocyclic backbone to modify the properties of the hosts, e.g., to increase rigidity and lipophilicity, (Marchand, A. P.; Huang, Z.; Chen, Z.; Hariprakasha, H. K.; Namboothiri, I. N. N.; Brodbelt, J. S.; Reyzer, M. L. J. Heterocyclic Chem. 2001, 38, 1361). The effect of increased rigidity introduced by the incorporated moiety can be interpreted in terms of preorganization. The principle of preorganization (Cram, D. J. in From Design to Discovery American Chemical Society, Washington D.C., 1991, p 9) states: The more highly hosts and guests are organized for binding and low solvation prior to complexation, the more stable will be the complexes.

(2) The topology, along with ring size determines the degree of preorganization of a specific structure for complexation. The general trend is that the two-dimensional structure develops into a three dimensional structure, wherein, for similar ring-size, the rigidity of the molecule increases. For example, rigidity increases along the series 18-crown-6, [2.2.2]-cryptand. Increasing rigidity in this way restricts the ability of the ligand to undergo conformational reorganization. Thus more rigid ligands are more highly preorganized. Since the host must undergo conformational adjustment to provide a proper binding environment during the host-guest interaction. Thus, preorganization of a ligand, which is associated with its topology, rigidity and solvation, becomes important. For a specific guest, the more highly preorganized ligand requires less conformational change and thus pays minimal energy cost for conformational adjustment.

(3) Increasing rigidity of the host the more highly preorganized host and the more highly host and guest are organized for binding the more stable the complexes will be.

(4) In order to attain high, yet selective binding of a potassium ion chelator some rigidity in the system such as the ionophore dibenzo-[2.2.2] cryptand was considered necessary.

(5) The cavity size of [2.2.2] cryptand (2.8 A in diameter) closely matches the size of potassium cation (2.66 A).

(6) Substituted [2.2.2] cryptands, such as dibenzo [2.2.2] cryptand, possess a guest binding site (ionophore) having heteroatom with nonbonding electron pairs such as nitrogen, capable of binding potassium (K.sup.+) selectively in its cavity.

(7) The synthesis of dibenzo-cryptand [2.2.2]; namely 4,7,13,16,20,23-hexaoxa-1,10-diaza-19(1,2),24(1,2)-dibenzabicyclo[8.8.6]tetracosaphane (VII) is outlined in Scheme 1. The commercially available 2-nitrophenol (I) was chosen as a starting material.

(8) Treatment of two equivalents of (I) with 1,2-dibromoethane and potassium carbonate in dimethyl formamide (DMF) afforded 1,2-Bis (2-nitrophenoxy)ethane (II). Reduction of (II) with 10% Palladium-on-charcoal as the catalyst produced the amino derivative (III). The diamine (III) was reacted with 3,6-dioxaoctanedioyl dichloride (1,2-ethylene-O,O-diglycolic acid chloride) in tetrahydrofuran (THF) at high dilution conditions in tetrahydrofuran (Dietrich, B.; Lehn, J. M.; Sauvage, J. P.; Blanzat, J. Cryptates. X. Syntheses and physical properties of diazapolyoxamacrobicyclic systems. Tetrahedron 1973, 29, 1629) to give the lactam (IV). The lactam (IV) was reduced with Lithium Aluminum Hydride (LiAlH.sub.4) in THF to give the azacrown (V) (Previously reported by de Silva, A. P.; Gunaratne, H. Q. N.; Samankumura, K. R. A. S. A new benzo-annelated cryptand and a derivative with alkali cation-sensitive fluorescence. Tetrahedron Lett. 1990, 31, 5193-5196). Subsequent treatment of (V) with 3,6-dioxaoctanedioyl dichloride gave (VI) which upon reduction with diborane in tetrahydrofuran (Pettit, W. A.; Iwai, Y.; Berfknecht, C. F.; Swenson, D. C. Synthesis and structure of N.sup.1-e-benzo-4,7,13,16,21,26-hexaoxa-1,10-diazabicyclo[8.8.8]hexacos-23-yl-N.sup.2-phenylthiourea. Derivative of a bifunctional complexing agent. J. Heterocycl. Chem 1992, 29, 877) furnished the cryptand (VII).

(9) The phenyl groups of cryptand VII can be further derivatized by further chemical reactions such as bromination. Bromination of (VII) with 2,4,4,6-tetrabromo-2,5-cyclohexadien-1-one afforded the dibromo-cryptand (VIII).

(10) The dibromo-cryptand (VIII) was also prepared by an alternative reaction sequence starting with azacrown (V). Bromination of (V) with bromine afforded both monobromo azacrown (IX) and dibromo azacrown (X). Treatment of (X) with 3,6-dioxaoctanedioyl dichloride afforded (XI) which upon reduction with Borane in THF gave the dibromo-cryptand (VIII). (Naguib, Y M A. Molecules 2009, 14, 3600-3609).

(11) ##STR00001## ##STR00002##

(12) Di-substituted [2.2.2] cryptand possesses a guest binding site (ionophore) having heteroatom with nonbonding electron pairs such as nitrogen, capable of binding potassium (K.sup.+) selectively in its cavity.

(13) Cryptand is a phase-transfer agent used to complex [.sup.18F] fluoride in non-aqueous environment to form [.sup.18F] fluoride cryptate complexes suitable for performing radio-labeling reactions to generate [.sup.18F] fluorinated species to be viewed through an imaging agent such as Positron Emmision Tomography (PET) and that a [.sup.18F] fluorinated species defined herein comprises chemical or biological [.sup.18F] fluorinated compounds for use as imaging agents.

(14) Several approaches for incorporating .sup.18F in biomolecules are described in the following references: Kuhnast, B., et al. (2004) J. Am. Chem. Soc., 15, 617-627; Garg, P. K., et al. (1991) Bioconj. Chem., 2, 44-49; Lee, B. C., et al. (2004) J. Am. Chem. Soc., 15, 104-111; Chen, X., et al. (2004) J. Am. Chem. Soc., 15, 41-49; Glaser, M., et al. (2004) J. Am. Chem. Soc., 15, 1447-1453; Toyokuni et al. Bioconjug. Chem. (2003) 14: 1253-9; and Couturier, O., et al. (2004) Eur. J. of Nuc. Med. and Mol. Imaging, 31, 1182-1206).

(15) The present invention is not to be limited in scope by specific to embodiments described herein. Indeed, various modifications of the inventions in addition to those described herein will become apparent to those skilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the appended claims.

(16) Various publications and patent applications are cited herein, the disclosures of which are incorporated by reference in their entireties.

REFERENCES

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