18F-LABELED BISPHOSPHONATES FOR PET IMAGING

Abstract

A novel method for rapidly and efficiently introducing fluorine into the P-C-P backbone of bisphosphonates starting from readily accessible diazomethylenebisphosphonate esters is provided. The method is applied successfully to create novel [.sup.18F]-labeled bisphosphonates for positron emission tomography imaging. Some versions of the method include reacting a diazomethylenebisphosphonate tetraalkyl ester with a fluorinating agent in the presence of an acidic HF/base complex and a t-butyl hypohalite to produce a halofluoromethylenebisphosphonate tetraalkyl ester, and dealkylating the halofluoromethylenebisphosphonate alkyl ester to produce a halofluoromethylenebis(phosphonic acid). Methods of replacing the halogen group with hydrogen are further provided. .sup.18F-labeled bisphosphonates prepared by the methods, and methods of using such compounds for positron emission tomography imaging in patients and animal models, are also provided.

Claims

1. A method of preparing a fluorinated bisphosphonate, comprising: reacting a compound of the formula (I) ##STR00018## with a fluorinating agent in the presence of an acidic HF/base complex and a t-butyl hypohalite (t-BuOX) to produce a compound of the formula (II), ##STR00019## and dealkylating the compound of the formula (II) to produce a halofluoromethylenebis(phosphonic acid) of the formula (III), ##STR00020## wherein X is halogen, each R is the same or different and is independently alkyl or benzyl, and, optionally, the fluorinating agent is H.sup.18F or a salt thereof, and F of the formulas (II) and (III) is .sup.18F.

2. The method of claim 1, wherein X is Cl or Br.

3. The method of claim 1, wherein the alkyl is C.sub.1-C.sub.3 alkyl.

4. The method of claim 1, wherein each R is the same.

5. The method of claim 1 wherein the fluorinating agent is HF or H.sup.18F, or a salt thereof.

6. The method of claim 5, wherein the salt is KF, NaF, CsF, Bu.sub.4NF, Et.sub.4NF, K.sup.18F, Na.sup.18F, Cs.sup.18F, Bu.sub.4N.sup.18F or Et.sub.4N.sup.18F.

7. The method of claim 1 wherein the base in the acidic HF/base complex is pyridine, triethylamine or 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU).

8. The method of claim 1, wherein a molar ratio of the compound of the formula (I): HF is in the range of about 1:0.05 to about 1:4.

9. The method of claim 1, wherein the t-butyl hypohalite is t-butyl hypochlorite or t-butyl hypobromite.

10. The method of claim 1, wherein the dealkylation is carried out by treatment with bromotrimethylsilane while heating, followed by hydrolysis with water or an alcohol.

11. The method of claim 10, further comprising microwave irradiation during the dealkylation.

12. The method of claim 1, wherein the halofluoromethylenebis(phosphonic acid) is selected from the group consisting of ##STR00021##

13. A method of preparing a fluoromethylenebis(phosphonic acid), comprising treating a compound of the formula (III) or (IIIa) ##STR00022## with a reducing agent to produce a fluoromethylenebis(phosphonic acid) of the formula (V) or (Va), respectively, ##STR00023## wherein X is halogen.

14. The method of claim 13, wherein X is Cl or Br.

15. A method of preparing a fluoromethylenebis(phosphonic acid), comprising: dehalogenating a compound of the formula (II) or (IIa) ##STR00024## with a reducing agent to produce a compound of the formula (IV) or (IVa), respectively, ##STR00025## and dealkylating the compound of the formula (IV) or (IVa) to a fluoromethylenebis(phosphonic acid) of the formula (V) or (Va), respectively, ##STR00026## wherein X is halogen, and each R is the same or different and is independently alkyl or benzyl.

16. The method of claim 15, wherein X is Cl or Br.

17. The method of claim 15, wherein the alkyl is a C.sub.1-C.sub.3 alkyl.

18. The method of claim 15, wherein each R is the same.

19. A method of preparing a fluorinated bisphosphonate, comprising: dealkylating a compound of the formula (I) ##STR00027## by treatment with bromotrimethylsilane to produce an intermediate tetrakis(trimethylsilyl) ester of the compound of formula (I), and reacting the intermediate with a fluorinating agent in the presence of an acidic HF/base complex and a t-butyl hypohalite (t-BuOX) to produce a compound of the formula (III) ##STR00028## wherein X is halogen and R is trimethylsilyl.

20. The method of claim 19, wherein the fluorinating agent is H.sup.18F or a salt thereof, and F of the formula (III) is .sup.18F.

21. A bisphosphonate compound prepared by the method of claim 1.

22. A bisphosphonate compound selected from the group consisting of ##STR00029## or a pharmaceutically acceptable salt thereof.

23. A pharmaceutical composition comprising one or any combination of the bisphosphonate compounds of claim 22, and a pharmaceutically acceptable carrier.

24. A method of in vivo positron emission tomography (PET) imaging, comprising injecting a subject with an aqueous solution comprising one or any combination of the .sup.18F-labeled bisphosphonate compounds of claim 22, and acquiring a PET scan of the subject.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0022] For a more complete understanding of the present invention, reference is now made to the following descriptions taken in conjunction with the accompanying drawings, in which:

[0023] FIG. 1 is an analytical HPLC profile of crude compound 7a.

[0024] FIG. 2 is a semi-preparative HPLC UV (top) and radioactivity (bottom) profile for. [.sup.18F]-ClFMBP.

[0025] FIG. 3 is a panel showing results after [.sup.18F]-ClFMBP injection. (3A) MicroPET images of a mouse at 2 hours post-injection. (3B) MicroPET quantification of major organs at 2 hours post-injection.

DETAILED DESCRIPTION

[0026] A common approach to the synthesis of -fluorinated bisphosphonates is electrophilic fluorination of the corresponding carbanions using N-fluoro reagents such as Selectfluor. [.sup.18F]-Selectfluor bis(triflate) has been prepared recently using high specific activity .sup.18F-F.sub.2 (19); however, [.sup.18F]-Selectfluor has not been yet widely adopted for [.sup.18F]-labeling due to the non-trivial requirement for an electrical discharge chamber (20). More generally, electrophilic fluorination of bisphosphonates is conventionally slow and cumbersome in the context of [.sup.18F]-syntheses, where total synthesis time is restricted by the short t.sub.1/2 of the radioisotope. Recently, Emer et al. reported an efficient nucleophilic .sup.18F-fluorination of 1-(diazo-2,2,2-trifluoroethyl)arenes with .sup.18F-labeled Olah reagent (21). However, the inventors' attempts to apply this procedure to several diazomethylenebisphosphonate esters were unsuccessful, possibly due to the lower reactivity of neutral diazo BPs (22). With a view to satisfying the [.sup.18F]-labeling desiderata of simplicity, rapidity and efficiently high yields, reaction of a diazomethylenebisphosphonate alkyl ester in the presence of t-butyl hypochlorite (t-BuOCl) (23) with F.sup. was considered. HF or an equivalent source of HF can provide both the labelling atom and a Bronsted acid to activate the t-BuOCl reagent. Olah's reagent (HF pyridine) offers a safe and convenient source of HF. The inventors succeeded in fluorinating diazo BPs using Olah reagent in the presence of t-BuOCl, resulting in the introduction of one chlorine atom and one fluorine atom. Based on the chloro compounds, this approach can be adapted to introduce one bromine atom and fluorine atom.

[0027] Scheme 1 describes the synthesis of halofluoromethylenebis(phosphonic acids) (6a, 6b) from diazomethylenebisphosphonate alkyl esters (e.g., 2 or 3) by the new method.

##STR00014##

[0028] In embodiments containing chloride compounds, diazomethylenebisphosphonate tetramethyl (2) and tetraethyl (3) esters, prepared according to the literature (24), were placed in a polypropylene tube with formulation of the corresponding solution of Olah reagent in dichloromethane (DCM). A slight excess of t-BuOCl (2.5 Eq) was added to the reaction mixture at 10 C. Upon warming to room temperature, the reaction proceeded with rapid evolution of N.sub.2, and formation of chlorofluoromethylenebisphosphonate (4a, 5a) in 87% and 82% yield, respectively by .sup.31P NMR and MS. A minor side product was identified as the dichloromethylenebisphosphonate ester (10-12%). The demethylation of 4a was easily accomplished by brief (15 min) reaction with bromotrimethylsilane (BTMS) (25) in acetonitrile at 80 C. followed by instantaneous conversion to the tetraacid by contact with water (or an alcohol) to afford chlorofluoromethylenebis(phosphonic acid) 6a in quantitative yield (Scheme 1). BTMS de-ethylation of 5a was also completed in 20 min, assisted by microwave irradiation at 60 C. Overall, the preparation of 6a was achieved in two fast and convenient steps from readily available starting materials.

[0029] Scheme 2 describes the synthesis of [.sup.18F]-ClFMBP 1a and [.sup.18F]-BrFMBP 1b by the novel method of radiolabeling diazomethylenebisphosphonate esters.

##STR00015##

[0030] The [.sup.18F]-labeling of tetraethyl and tetramethyl bisphosphonate esters can be carried out according to the method under various conditions. For example, [.sup.18F]-poly(hydrogen fluoride)pyridinium (H.sup.18F/Py), prepared according to a previously reported procedure (26), was used in [.sup.18F] radiofluorinations of bisphosphonate esters and the intermediate product was analyzed by analytical HPLC. When tetraethyl bisphosphonate ester (3, 7 mg) was mixed with H.sup.18F/Py (10 L) and t-butyl hypochlorite (15 L), the radiofluorination was completed within 1 min with cessation of N.sub.2 evolution. The desired tetraethyl chloro[.sup.18F]-fluoromethylenebisphosphonate 8a was formed in 56% radiochemical yield (RCY), which was not improved by using greater excess of the reagents. As BTMS dealkylation of the tetraethyl ester required a longer heating time (or microwave irradiation assistance) (27, 28), radiofluorination of tetramethyl bisphosphonate ester 2 was found to be advantageous. Excess of H.sup.18F/Py decreased the RCY, which may be due to the instability of tetramethyl diazomethylenebisphosphonate 2 in the presence of excess HF reagent. Tetramethyl diazomethylenebisphosphonate (2, 5.5 mg), H.sup.18F/Py (15 L), and t-BuOCl (15 L) provided 7a with the highest RCY (55.3%). After semi-preparative HPLC purification, 7a was obtained in 458% RCY (decay-corrected, n=3).

[0031] Demethylation of 7a followed the conditions established for the .sup.19F-containing tetramethyl ester 4a. A mixture of 7a in acetonitrile and BTMS (1:1 ratio) was heated for 15 min at 80 C. affording after hydrolysis [.sup.18F]-ClFMBP (1a). The radiochemical purity of [.sup.18F]-ClFMBP was determined to be >99%. The specific activity of the final product was estimated to be 11.7 mCi/mol.

[0032] Based on the chloride compounds, these methods can be adapted to prepare unlabeled and [.sup.18F]-labeled BrFMBP compounds, e.g. 7b, 8b and 1b.

[0033] Scheme 3 describes the synthesis of [.sup.18F]-FMBP by reduction of [.sup.18F]-ClFMBP or [.sup.18F]-BrFMBP.

##STR00016##

[0034] Compounds 1la or 1b can be used to synthesize [.sup.18F]-FMBP (compound 9) by replacing the chlorine or bromine atom in either starting compound by a hydrogen atom. This replacement can be effected rapidly by use of a suitable reducing agent (RA) under appropriate conditions, as shown in Scheme 3. An example of such a reducing agent might be excess aqueous sodium dithionite applied at a temperature between room temperature and 90 C. for a period of less than 30 min. Examples of other reducing agents include, but are not limited to, SnCl.sub.2 or NaHSO.sub.3 (30), or H.sub.2/Pd/C or H.sub.2/PtO.sub.2.

[0035] Alternatively, Scheme 4 describes the synthesis of [.sup.18F]-FMBP by selective dehalogenation of [.sup.18F]-ClFMBP or [.sup.18F]-BrFMBP alkyl or benzyl esters, followed by dealkylation.

##STR00017##

[0036] In this alternative method, compound 9 can be synthesized in two steps, beginning with a tetraalkyl ester of [.sup.18F]-ClFMBP or [.sup.18F]-BrFMBP, as shown in Scheme 4 (methyl or ethyl esters 7 or 8 are illustrated, however any alkyl group may be used, particularly any C1-C3 alkyl, or benzyl group). In this approach, the ester may be advantageously dissolved in an organic solvent, e.g. THF or acetonitrile. Selective dehalogenation of the starting ester may be effected by a suitable reducing agent, such as dithionite in a mixed aqueous-organic solvent system with or without a phase transfer catalyst at or somewhat above room temperature for less than 30 min, or alternatively by treatment with 1:1 or a slight excess of a salt of a carbon compound, e.g. butyl lithium as shown in Scheme 4, at low temperatures in an organic solvent such as THF, for a brief period not exceeding 5 min. Other ways of dehalogenation include, but are not limited to hydrogenolysis catalyzed by Pd or PtO.sub.2. The resulting [.sup.18F]-MBP alkyl ester (such as 10 or 11 in Scheme 4) can then be readily dealkylated to form [.sup.18F]-MBP or a salt thereof, using a method already provided herein, as in Scheme 4.

[0037] A fluorine-labeled bisphosphonate can be prepared as a salt, which may be a physiologically acceptable salt or a pharmaceutically acceptable salt. Physiologically acceptable salts and pharmaceutically acceptable salts are well known in the art. Salts formed with, for example, a POH group, can be derived from inorganic bases including, but not limited to, sodium, potassium, ammonium, calcium or ferric hydroxides, and organic bases including, but not limited to, isopropylamine, trimethylamine, histidine, and procaine.

[0038] In embodiments involving imaging, the composition may comprise an effective amount of a fluorine-labeled bisphosphonate, or a salt thereof, which can be a physiologically acceptable or pharmaceutically acceptable salt thereof. An effective amount of a compound is an amount that gives emission signals sufficient for PET imaging. As is known, the amount will vary depending on such particulars as the condition of the target tissue, the particular bisphosphonate utilized, and the characteristics of the patient.

[0039] Physiologically acceptable carriers and/or diluents, and pharmaceutically acceptable carriers and/or diluents, are familiar to those skilled in the art. For compositions formulated as liquid solutions, acceptable carriers and/or diluents include saline and sterile water, and may optionally include antioxidants, buffers, bacteriostats and other common additives. One skilled in this art may further formulate the compound in an appropriate manner, and in accordance with accepted practices, such as those disclosed in Remington's Pharmaceutical Sciences, Gennaro, Ed., Mack Publishing Co., Easton, Pa. 1990.

[0040] Liquid pharmaceutically administrable compositions may, for example, be prepared by dissolving, dispersing, etc., an active compound as described herein and optional pharmaceutical adjuvants in an excipient, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form a solution or suspension. If desired, the pharmaceutical composition to be administered may also contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan mono-laurate, triethanolamine acetate, triethanolamine oleate, etc. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art.

[0041] The present invention may be better understood by referring to the accompanying examples, which are intended for illustration purposes only and should not in any sense be construed as limiting the scope of the invention.

EXAMPLE 1

General Materials and Methods

[0042] All the solvents were removed under vacuum at 2 torr. .sup.31P NMR and .sup.19F NMR were recorded on a VNMRS-500 MHz instrument using external D.sub.2O as locking solvent and the .sup.31P NMR and .sup.19F NMR chemical shifts were corrected using 85% phosphoric acid in D.sub.2O ( 0.00) and hexafluorobenzene (-164.9) respectively. Data for .sup.31P NMR and .sup.19F NMR are recorded as follows: chemical shift (, ppm), multiplicity (s=singlet, d=doublet, t=triplet). Mass spectrometry (MS) was performed on a Finnigan LCQ Deca XP Max low resolution mass spectrometer equipped with an ESI source in the negative ion mode.

Cold Chemistry

Preparation of Starting Materials

[0043] Diazomethylenebisphosphonates (2, 3) were prepared according to literature..sup.24 t-Butyl hypochlorite was prepared according to the previously reported procedure..sup.29 HF in pyridine and bromotrimethylsilane (BTMS) were directly purchased from Aldrich. BTMS was distilled under nitrogen. Dry DCM and acetonitrile were directly purchased from VWR (drisolv).

General Procedure for the Preparation of 4 or 5

[0044] 2 or 3 (320 mmol) was dissolved in 0.5 ml of dry DCM in a polypropylene Eppendorf tube. 37 L of a solution of HF in pyridine (4 eq) was added and the mixture was cooled down to 10 C. 100 L of t-butyl hypochlorite (2.5 eq) was added. After slight warming to room temperature, the reaction proceeded rapidly with evolution of nitrogen. After the evolution of nitrogen stopped (1 min), the solution was washed with 1 mL of saturated sodium carbonate solution and then washed with water (22 ml) and dried over 300 mg anhydrous sodium sulfate and the solvent was removed under vacuum and used for the next reaction without further purification.

[0045] Yield: compound 4a, 87% (by .sup.31P NMR). .sup.31P NMR (202 MHz, D.sub.2O) 9.86, 7.37 (d, J=74.1 Hz); .sup.19F NMR (470 MHz, CDCl.sub.3) -144.16 (t, J=75.3 Hz).

[0046] Yield: compound 5a, 82% (by .sup.31P NMR). .sup.31P NMR (202 MHz, D.sub.2O) 8.06, 5.56 (d, J=78.2 Hz); .sup.19F NMR (470 MHz, CDCl.sub.3) -146.91 (t, J=74.4 Hz).

General Procedure for the Preparation of 6a

[0047] The product residue 4a or 5a was dissolved in 0.2 mL dry acetonitrile and freshly distilled BTMS (Aldrich 97% stabilized by silver, 200 L, (24 eq) was added and the reaction was set to reflux. Dealkylation was completed at 80 C. after 15 min. The solvent was then removed by evaporation under vacuum and the residue was treated with methanol, giving after removal of the solvent under vacuum, the product acid 6a in quantitative yield. .sup.19F NMR (470 MHz, D.sub.2O) -145.48 (t, J=76.9 Hz). MS calcd for CH.sub.3ClFO.sub.6P2.sup.: 226.91 (100.0%), 228.91 (32.0%), [M-H].sup., found: 227.32 (100.0%), 229.35 (32.0%), MS calcd for CH.sub.3Cl.sub.2O.sub.6P.sub.2.sup.: 242.88 (100.0%), 244.88 (63.9%), [M-H].sup., found: 243.10 (100.0%), 245.30 (64.0%).

Radiochemistry Experiment

[0048] All chemicals were purchased in analytical grade and used without further purification. Analytical reversed-phase high performance liquid chromatography (HPLC) with a Phenomenex Luna C18 reversed phase column (2504.6 mm, 5 micron) was performed on a Dionex UltiMate 3000 system (Thermo Fisher Scientific, Inc.). The flow was 1 mL/min, with the mobile phase starting from 100% solvent A (0.1% TFA in water) for 5 min, followed by a gradient mobile phase to 20% solvent A and 80% solvent B (0.1% TFA in acetonitrile) at 6 min and isocratic mobile phase with 80% solvent B until 15 min. The UV absorbance was monitored at 254 nm. The radioactivity was detected by a model of Ludlum 2200 single-channel radiation detector. Semi-preparative reversed phase HPLC with a Phenomenex Luna C18 reversed phase column (25010 mm, 5 m) was carried out on a Knauer BlueShadow Integrated LPG System (Bay Scientific, Inc.). The flow rate was 4 mL/min, with the mobile phase starting from 100% solvent A (0.1% TFA in water) for 7 min, followed by a gradient mobile phase to 20% solvent A and 80% solvent B (0.1% TFA in acetonitrile) at 8 min and isocratic mobile phase with 80% solvent B until 18 min. The UV absorbance was monitored at 254 nm. The radioactivity was detected by a solid-state radiation detector (Carroll & Ramsey Associates).

Radiochemistry

[0049] The radiolabeling reactions were carried out using the following protocol unless otherwise specified.

Radiosynthesis of [.SUP.18.F]-poly(hydrogen fluoride)pyridinium

[0050] Cyclotron-produced [.sup.18F] fluoride ion (0.74-1.85 GBq) in [.sup.18O] water was passed through a pre-conditioned QMA cartridge (ABX GmbH, Germany). After removal of [.sup.18O] water, the retained [.sup.18F]fluoride was eluted with an aqueous solution of K.sub.2CO.sub.3 (2.3 mg in 400 L). The solution was then evaporated to remove water and provide anhydrous [.sup.18F]-KF. Then, 15 L of (HF).sub.n pyridinium was added, and the solution was incubated at room temperature for 15 min so that the radioactivity can be incorporated into the perfluorinating agent. The solution was used for the next step without further purification.

Radiosynthesis of tetramethyl (chloro[.SUP.18.F]-fluoromethylene)bisphosphonate (7a)

[0051] To an Eppendorf tube containing tetramethyl diazomethylenebisphosphonate (5.5 mg) dissolved in 50 L of dry dichloromethane, [.sup.18F]-poly(hydrogen fluoride)pyridinium (15 L) was added. The mixture was then cooled to 10 C. using dry ice, and 15 L of t-butyl hypochlorite was added into the mixture. After the evolution of nitrogen stopped (<1 min), the solution was evaporated under reduced pressure. The residue was re-dissolved in 20% acetonitrile in water, and analyzed by analytical HPLC. The radiofluorinated 7a was eluted out at 9.78 min. The HPLC result of crude 7a is shown in FIG. 1. The radiofluorinated 7a was purified by semi-preparative HPLC and eluted out at 13.2 min.

Radiosynthesis of (chloro[.SUP.18.F]-fluoromethylene)bisphosphonic acid ([.SUP.18.F]-ClFMBP)

[0052] To the solution containing 7a in 200 L of acetonitrile, 200 L of bromotrimethylsilane (BTMS) was added. The mixture was heated at 80 C. for 15 min. After the reaction was completed, volatiles were removed by evaporation under vacuum, and 0.5 mL of deionized water was added into the residue. The reaction mixture was then loaded onto semi-preparative HPLC for purification. The HPLC fraction containing [.sup.18F]-ClFMBP (t.sub.R=3.6 min) was collected. The HPLC result is shown in FIG. 2. The HPLC eluent was removed using a rotary evaporator. [.sup.18F]-ClFMBP was then reconstituted in 0.9% sodium chloride injection solution and adjusted to pH 7.0. The specific activity of the final product was estimated to be 11.7 mCi/mol based on 20% conversion of 7a from [.sup.18F]-poly(hydrogen fluoride)pyridinium. The final product was passed through a 0.22-m Millipore filter into a sterile vial for small animal study.

Animals

[0053] All animal studies were approved by the University of Southern California Institutional Animal Care and Use Committee. Female athymic nude mice (about 4-6 weeks old, with a body weight of 20-25 g) were obtained from Harlan Laboratories (Livermore, Calif.). MicroPET scans were performed using an Inveon microPET scanner (Siemens Medical Solutions, Malvern, Pa., USA). A normal nude mouse was anesthetized using 2% isoflurane and injected with 1.3-2.5 MBq of [.sup.18F]-ClFMBP via tail vein. At 0.5, 1, and 2 h post injection, static emission scans were acquired for 10 min. Raw PET images were reconstructed using 2D ordered subset expectation maximization (OSEM) algorithms with scatter, random and attenuation correction.

EXAMPLE 2

[0054] FIG. 3A shows MicroPET images of a mouse at 2 h post-injection of purified [.sup.18F]-ClFMBP. In order to demonstrate its potential for in vivo PET imaging, [.sup.18F]-ClFMBP was injected into normal nude mice that were imaged using a microPET scanner at 0.5, 1, and 2 h post-injection. The joints and bones were clearly visible with high contrast to contralateral background at all of imaging time points. The 2D projection of PET images at 2 h post-injection is shown. Predominant uptake of radioactivity was also observed in the bladder, suggesting the excretion of [.sup.18F]-ClFMBP is mainly through the renal system.

[0055] FIG. 3B shows MicroPET quantification of major organs at 2 h post-injection of purified [.sup.18F]-ClFMBP. At 2 h post-injection, the uptake of [.sup.18F]-ClFMBP in mouse liver and kidneys was calculated to be 0.210.04 and 0.160.08% ID/g (% injected dose per gram of tissue), respectively, which are significantly lower than the values in joints (2.370.08% ID/g) and bones (2.720.05% ID/g). Accumulation of [.sup.18F]-ClFMBP in other mouse organs was minimal.

REFERENCES

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[0087] Although the present invention has been described in connection with the preferred embodiments, it is to be understood that modifications and variations may be utilized without departing from the principles and scope of the invention, as those skilled in the art will readily understand. Accordingly, such modifications may be practiced within the scope of the invention and the following claims.