The nucleoside analog 2'-fluoro-5-methyl-1-.beta.-D-arabinofuranosyluracil (FMAU) has been found to have an especially desirable combination of properties for use as an imaging agent, including in particular limited in vivo catabolism. Methods for the preparation of the [.sup.11 C]-and [.sup.18 F]-labeled FMAU and for the use of the labeled material are also provided.

FIELD OF THE INVENTION
 This invention relates generally to the fields of biochemistry and
 medicine. More particularly, the present invention relates to compositions
 for use in imaging cancer or infectious disease.
 BACKGROUND OF THE INVENTION
 Imaging of cellular proliferation in vivo using radiolabeled analogues of
 nucleosides such as [.sup.131 I]-IUdR and [.sup.11 C]-thymidine is plagued
 by extensive catabolism of the parent compounds following intravenous
 administration, limiting uptake into the DNA of tumor tissues. Such
 catabolic events include dehalogenation, cleavage of the sugar moieties
 from the base, and ring opening of the base. In vivo assessment of such
 events requires complex mathematical models to interpret kinetic data
 obtained in imaging studies.
 Mathematical models currently being designed to interpret positron emission
 tomography (PET) kinetic data obtained from [.sup.11 C] thymidine studies
 in tumors are generally cumbersome, in large measure due to the presence
 of significant levels of short-term catabolism of thymidine with
 subsequent production of several radiolabeled byproducts in plasma and
 tissue {Martiat, P. H., et al., "In vivo measurement of carbon-11
 thymidine uptake in non-Hodgkin's lymphoma using positron emission
 tomography", J. Nucl. Med., 29:1633-1637 (1988); Shields, A. F., et al.,
 "Short-term thymidine uptake in normal and neoplastic tissues: Studies for
 PET," J. Nucl. Med., 25:759-764 (1984); Shields, A. F., et al., "Cellular
 sources of thymidine nucleotides: Studies for PET", J. Nucl. Med.
 28:1435-1440 (1987); Wong, C.Y.O., et al., "[.sup.11 C]-Thymidine PET
 imaging as a measure of DNA synthesis rate: A preliminary quantitative
 study of human brain glioblastoma", J. Nucl. Med., 35:9P (1994); Mankoff,
 D. A., et al., "Graphical analysis method for estimating blood-to-tissue
 transfer constants for tracers with labeled metabolites", J. Nucl. Med.,
 35:34P (1994a); Mankoff, D. A., et al., "Tracer kinetic model to
 quantitative imaging of thymidine utilization using [.sup.11 C]-thymidine
 and PET", J. Nucl. Med. 35, 138P (1994b)}. Though potentially less
 complex, modeling of the kinetic behavior of ring labeled thymidine is
 likewise non-trivial {Shields A. F., et al., "Use of [.sup.11 C]-thymidine
 with PET and kinetic modeling to produce images of DNA synthesis", J.
 Nucl. Med., 33:1009-1010 (1992); Mankoff, D. A., et al. (1994a, b),
 supra}. In the case of imaging studies with radioiodinated IUdR using
 conventional nuclear medicine techniques, in addition to significant
 dehalogenation it has also been demonstrated that UdR, once formed, may be
 converted to TdR in mammalian systems and subsequently incorporated into
 DNA {Commerford, S. L., et al., "lododeoxyuridine administered to mice is
 de-iodinated and incorporated into DNA primarily as thymidylate", Biochem.
 Biophys. Res. Comm., 86:112-118 (1979)}.
 The short-term catabolism of [.sup.11 C and .sup.14 C-methyl]-thymidine
 have been extensively studied {Conti, P. S., et al., "Tumor imaging with
 positron-emission tomography (PET) and [.sup.11 C]-thymidine:
 Determination of radiolabeled thymidine metabolites by high pressure
 liquid chromatography (HPLC) for kinetic data analysis", Radiology,
 173:P402 (1989); Conti, P. S., et al., "Analysis of nucleoside metabolism
 during positron emission tomography (PET) imaging studies of brain tumors
 with carbon-11 labeled thymidine (TdR)", 199th Meeting of American
 Chemical Society, Boston, Mass., Apr. 22-27 (1990)}. Such studies have
 demonstrated that significant catabolism occurs once thymidine has been
 administered intravenously, with the notable radiolabeled products being
 thymine, dihydrothymine, beta-ureidoisobutyric acid, and
 beta-aminoisobutyric acid. The latter constitutes the most abundant
 radiolabeled species in plasma and tissues by 10 minutes post-injection.
 While [.sup.11 C]-CO.sub.2 is the most abundant radiolabeled species in
 plasma following administration of ring labeled thymidine {Shields, A. F.,
 et al., "Comparison of PET imaging using [.sup.11 C]-thymidine labeled in
 the ring-2 and methyl positions", J. Nucl. Med., 31:794 (1990); Shields A.
 F., et al., "Contribution of labeled carbon dioxide to PET imaging of
 [.sup.11 C]-labeled compounds", J. Nucl. Med., 31:909 (1990)},
 radiolabeled thymine, dihydrothymine, and beta-ureidoisobutyric acid also
 are present, albeit in lesser amounts. Despite its extensive catabolism,
 it has been demonstrated that [.sup.11 C]-thymidine has utility in tumor
 imaging in both animal models and patients {Larson, S. M., et al.,
 "Positron imaging feasibility studies. I: Characteristics of [.sup.3
 H]-thymidine uptake in rodent and canine neoplasms: Concise
 Communication", J. Nucl. Med., 22:869-874 (1981); Conti, P. S., et al.,
 "Potential use of carbon-11 labeled thymidine (TdR) for studying the
 effect of therapy on prostatic adenocarcinoma in vivo", 32nd Annual
 Meeting of the Radiation Research Society, Orlando, Fla., Mar. 25-29
 (1984); Conti, P. S., et al., "Comparative uptake studies of radiolabeled
 thymidine in the Dunning R3327H fast-growing and R3327H slow-growing
 prostate adenocarcinomas in vivo", 79th Meeting of the American Urological
 Association, New Orleans, La., May 6-10 (1984); Conti, P. S., et al.,
 "Carbon-11 labeled alpha-aminoisobutyric acid, 2-deoxy-D-glucose and
 thymidine as potential imaging agents for prostatic and renal
 malignancies", Surgical Forum, 36:635-637 1985); Conti, P. S., et al.,
 "Multiple radiotracers for evaluation of intracranial mass lesions using
 PET", J. Nucl. Med., 32:954 (1991); Shields, A. F., et al.(1984, 1987,
 1990b, c), supra; Shields A. F., et al., "Utilization of labeled thymidine
 in DNA synthesis: Studies for PET", J. Nucl. Med., 31:337-342 (1990);
 Martiat, P. J., et al. (1988), supra; Strauss, L. G. et al., "The
 applications of PET in clinical oncology",. J. Nucl. Med., 32:623-648
 (1991); Schmall B., et al, "Tumor and organ biochemical profiles
 determined in vivo following uptake of a combination of radiolabeled
 substrates: Potential applications for PET", Amer. J. Phys. Imag., 7:2-11
 (1992); Wong, C.Y.O., et al. (1994), supra; Vander Borght T., et al.,
 "Brain tumor imaging with PET and 2-[.sup.11 C]-thymidine", J. Nucl. Med.,
 35:974-982 (1994)}.
 There is thus a long-felt need in the art for a suitable partially or
 non-catabolized imaging agent (e.g., nucleoside analog) for use in, e.g.,
 tumor proliferation studies with PET. Except for limited catabolism, an
 ideal tracer should share the other in vivo characteristics of thymidine,
 including cell transport, phosphorylation by mammalian kinase, and
 incorporation into DNA. In particular, development of a partially or
 non-catabolized thymidine analog would greatly simplify imaging and
 modeling approaches and potentially provide higher tumor to target ratios
 due to more selective incorporation of radiotracer.
 It is an object of the present invention to provide compositions and
 methods which do not suffer from the drawbacks of the heretofore-known
 compositions.
 SUMMARY OF THE INVENTION
 The present invention is directed to compositions and methods that can be
 used for in vivo imaging of proliferating cells. The composition includes
 an imaging agent, which is a 2'-deoxy-2'-fluoro-D-arabinofuranosyl
 pyrimidine nucleoside analog, and a physiologically acceptable carrier or
 adjuvant. The imaging agent is labeled with a positron emitting
 radioisotope, such as [.sup.11 C] or [.sup.18 F]. A unit dose of imaging
 agent is a non-toxic amount of the 2'-deoxy-2'-fluoro-D-arabinofuranosyl
 pyrimidine nucleoside analog, which is capable of localizing in
 proliferating cells and being detected in vivo.
 The method of imaging proliferating cells in vivo includes the steps of
 administering a unit dose of the imaging agent, which has been labeled
 with a positron emitting radioisotope like [.sup.11 C] or [.sup.18 F]. The
 imaging agent becomes localized in proliferating cells and is detected by
 nuclear medicine techniques, such as positron emission tomography (PET).
 The nucleoside analog 2'-fluoro-5-methyl-1-.beta.-D-arabinofuranosyluracil
 (FMAU) has been found to have an especially desirable combination of
 properties for use as an imaging agent, including in particular limited in
 vivo catabolism. Methods for the preparation of the [.sup.11 C]-and
 [.sup.18 F]-labeled FMAU and for the use of the labeled material are also
 provided.

DETAILED DESCRIPTION OF THE INVENTION
 Over the last decade, much research has been directed to exploring the
 radiosynthesis and in vivo pharmacology of antiviral and antileukemic
 nucleoside derivatives, including agents such as [.sup.125
 I]2'-fluoro-5-iodo-1-.beta.-D-arabinofuranosyl-cytosine (FIAC) {Perlman,
 M. F., et al., "Synthesis and purification of the antiviral agent
 1-(2-deoxy-2-fluoro-.beta.-D-arabinofuranosyl)-5-iodocytosine (FIAC)
 labeled with iodine-125", lnt. J. Nucl. Med. Biol., 11:215-218 (1984)},
 [.sup.125 I, .sup.131 I, .sup.123 I]
 2'-fluoro-5-iodo1-.beta.-D-arabinofuranosyl-uracils (FIAU) {Misra, H. K.,
 et al., "Synthesis of [.sup.131 I, .sup.125 I, .sup.123 I and .sup.82
 Br]-labeled 5-halo-1-(2-Deoxy-2-fluoro-.beta.-D-arabinofuranosyl)uracils",
 Appl. Radiated IST, 37:901-905 (1986)}, [.sup.11 C-N-methyl] acyclovir
 {Wilson, A. A., et al., "Radiosynthesis of [.sup.11 C]-N-methyl
 acyclovir", J. Lab. Compd. Radiopharm. 29, 765-768 (1991)}, and a
 [[.sup.11 C] or [.sup.18 F] derivative of
 9-[(1,3-dihydroxy-2propoxy)methyl] guanine (DHPG) {Alauddin M. M., et al.,
 "A novel synthesis suitable for labeling the antiviral agent
 9-[(3-fluoro-1-hydroxy-2-propoxy)methyl] guanine (FHPG) with [.sup.18 F]
 for in vivo imaging by positron emission tomography", 206th Meeting of the
 American Chemical Society, Chicago, Ill. Aug. 22-26 (1993a)}. Although
 some of these agents have potential utility in imaging cancer and/or
 infectious diseases, many undergo some form of catabolism leading to
 either loss of radiolabel or formation of multiple radiolabeled
 by-products. For example, administration of [.sup.125 I] labeled FIAC
 results in extensive deiodination in vivo {Perlman, et al. (1984), supra}.
 In addition, FIAU can be formed in vivo from deamination of administered
 FIAC {Chou, T-C, et al., "Pharmacological disposition and metabolic fate
 of 2'-fluoro-5-iodo-1-.beta.-D-arabinofuranosyl-cytosine in mice and
 rats", Cancer Res., 41:3336-3342 (1981); Grant, A. J., et al.,
 "Incorporation of metabolites of
 2'-fluoro-5-iodo1-.beta.-D-arabinofuranosylcytosine into deoxyribonucleic
 acid of neoplastic and normal mammalian tissues", Biochem. Pharm.
 31:1103-1108 (1982)}. A similar situation to IUdR also exists during the
 metabolism of FIAU. Although FIAU is less likely than IUdR to be
 catabolized by enzymatic cleavage of the glycosyl-base bond due to reasons
 discussed below, and can itself be incorporated into DNA, deiodination
 followed by methylation at the 5 position of the base also can occur prior
 to DNA incorporation {Chou, et al., (1981), supra; Grant, et al, (1982),
 supra}.
 Pursuant to the present invention, the antiviral and antileukemic agent,
 2'-fluoro-5-methyl-1-.beta.-D-arabinofuranosyluracil (FMAU) is
 demonstrated to be ideally suited as an in vivo radiotracer of cellular
 proliferation without the presence of complicated catabolism. FMAU has
 been shown to be phosphorylated by both mammalian and viral kinases,
 serving as a good substrate relative to thymidine in cell culture systems
 {Chou, T-C., et al., "Synthesis and biological effects of
 2'-fluoro-5-ethyl1-.beta.-D-arabinofuranosyluracil", Antimicrob. Agents
 Chemother., 31:1355-1358 (1987); Fox, J. J., et al., "Antiviral activities
 of 2'-fluorinated arabinosyl-pyrimidine nucleosides", in: Fluorinated
 Carbohydrates (Ed. N. F. Taylor, American Chemical Society, Washington,
 D.C.) Chapter 10, pp. 176-190 (1987)}. FMAU is transported into cells and
 phosphorylated by mammalian kinases to levels approaching that of
 thymidine, displaying substantial incorporation of [2-.sup.14 C]-FMAU into
 host DNA, and an ED.sub.50 of 8-28 .mu.M for inhibition of thymidine
 incorporation {Chou, et al. (1987), supra}. Accumulation of [2-.sup.14
 C]-FMAU has also been preferentially observed in organs with rapidly
 dividing cells such as the small intestine and spleen of rats, as well as
 in proliferating PC12 and Vero cells in culture {Saito Y., et al.,
 "Diagnostic imaging of herpes simplex virus encephalitis using a
 radiolabeled antiviral drug: autoradiographic assessment in an animal
 model", Ann. Neurol., 15:548-558 (1984)}.
 Nearly all injected radioactivity of intravenously administered [.sup.14
 C]-FMAU into mice, rats and dogs is cleared into the urine [Philips, F.
 S., et al., "Distribution, metabolism, and excretion of
 1-(2-fluoro-2-deoxy-.beta.-D-arabinofuranosyl)thymine and
 1-(2-fluoro-2-deoxy-.beta.-D-arabinofuranosyl)5-iodocytosine", Cancer
 Res., 43:3619-3627 (1983)}. In all three species, urine radioactivity
 through 24 hours is composed primarily of unchanged parent compound as
 determined by HPLC following intravenous administration of [2-.sup.14
 C]-FMAU {Philips, et al. (1983), supra}. Four minor metabolites have been
 detected in mouse, rat, and dog urine at 24 hr accounting for less than 3%
 (dogs), 5% (rats) and 15% (mice) of total urine radioactivity. One
 metabolite has been identified as the 5-hydroxymethyl derivative of FMAU
 {Philips, et al., (1983), supra; Feinberg, A., et al.,
 "2'-Fluoro-5-methyl-1-.beta.-D-arabinosyluracil (FMAU), a potent antiviral
 agent is metabolized in mice to
 2'-fluoro-5-hydroxymethyl-1-.beta.-D-arabinosyluracil and to an FMAU
 adduct", Proc. Amer. Assoc. Cancer Res., p46 (1983)}. Of these trace
 metabolites, a glucuronide adduct of FMAU, while present in all three
 species, appears to be most abundant in dogs {Philips, et al. (1983),
 supra; Feinberg, et al. (1983), supra; Feinberg, A., et al., "Structures
 of metabolites isolated from urine of mice treated with the antiviral
 agent, 1-(2'-deoxy-2'-fluoro-1-.beta.-D-arabinofuranosyl)-5-methyluracil",
 Drug Metab. Disp., 12:784-786 (1984)}.
 Ab initio studies using quantum-chemical methods have been used to explain
 the lack of significant catabolism of this compound, as well as its
 ability to be phosphorylated and incorporated into DNA. These studies have
 suggested that the fluorine atom in the sugar moiety locks the sugar-base
 bond in the anti conformation {Sapse, A. M., et al., "Ab initio studies of
 the antiviral drug 1-(2-fluoro-2-deoxy-.beta.-D-arabinofuranosyl)thymine",
 Cancer Invest., 3:115-121 (1985)}. While the fluorine atom is similar
 enough to hydrogen, with respect to van der Waals radii, to allow action
 by the polymerase leading to incorporation into DNA, it is suggested that
 it is large enough also to sterically hinder the rotation of the base
 around the sugar-base bond. Likewise, the locked anti-conformation
 probably enhances exposure to the DNA polymerase. Resistance to cleavage
 of the glycosyl bond by phosphorylase may be secondary to the
 electrostatic attraction of the fluorine atom on the C.sub.2 ' to the
 positive guanidinium group of an arginine responsible for bond cleavage at
 the active site of the enzyme. The ribo-isomer, on the other hand,
 exhibits a 1000-fold diminished biological activity.
 Two Phase I trials to evaluate the clinical efficacy of FMAU as an
 antineoplastic agent have been conducted {Abbruzzese, J. L., et al.,
 "Phase I trial of
 1-(2'-deoxy-2'-fluoro-1-.beta.-D-arabinofuranosyl)-5-methyluracil (FMAU)
 terminated by severe neurologic toxicity", Invest. New Drugs, 7:195-201
 (1989); Fanucchi, M. P., et al., "Phase I trial of
 1-(2'-deoxy-2'-fluoro-1-.beta.-D-arabinofuranosyl)-5-methyluracil (FMAU)",
 Cancer Treat. Rep., 69:55-59 (1985)}. Significant dose-limiting
 neurotoxicity developed in patients treated with doses above 8
 mg/m.sup.2.times.5 days {Abbruzzese, et al. (1989), supra}. Preclinical
 toxicology studies in dogs previously demonstrated an LD.sub.10 of 25
 mg/m.sup.2.times.10 days {Fannuchi, et al. (1985), supra}.
 The specific activities of the radiolabeled
 2'-deoxy-2'-fluoro-D-arabinofuranosyl pyrimidine nucleosides prepared in
 accordance with the present invention will generally range from about 50
 to about 100 Ci/mmol. Between 50-100 .mu.g of unlabeled FMAU would be
 administered intravenously into humans using 20 mCi doses of material with
 this specific activity, although somewhat larger or smaller doses may be
 appropriate in particular instances, as would be appreciated by those
 working in the field. For example, the half life of .sup.18 F is about 110
 minutes, whereas the half-life of .sup.11 C is only about 20.4 minutes.
 Accordingly, a unit dose of about 5 to 10 mCi .sup.18 F-FMAU would be
 sufficient, whereas a somewhat larger dose of up to about 25 mCi of
 .sup.11 C-FMAU would be appropriate. These tracer level dosages are
 approximately 1000-fold less than the minimum therapeutic dose noted to
 cause significant side effects in patients {Abbruzzese, et al. (1989),
 supra; Fannuchi, et al. (1985), supra}. Administration of the agents and
 their use in imaging (for example, using positron emission tomography)
 would be routine for those skilled in the imaging art.
 The synthesis of [.sup.11 C-methyl]-FMAU described herein was based broadly
 on a previously developed procedure for [.sup.11 C-methyl]-thymidine
 {Sundoro-Wu, B. M., et al. "Selective alkylation of pyrimidyl-dianions:
 Synthesis and HPLC of carbon-11 labeled thymidine for tumor visualization
 using positron emission tomography", Int. J. Appl. Radiated. IST.,
 35:705-708 (1984a); Sundoro-Wu, B. M., et al., "Selective alkylation
 suitable for labeling the antiviral agent
 2'-fluoro-5-methyl-1-.beta.-D-arabinofuranosyluracil (FMAU) with carbon-11
 for use in in vivo imaging", 187th National Meeting of the American
 Chemical Society, St. Louis, Mo., Apr. 8-13 (1984b)} with some
 modifications {Alauddin, M. M., et al., "Synthesis of high specific
 activity [.sup.11 C-methyl]-thymidine for in vivo imaging by positron
 emission tomography", 19th American Chemical Society Western Regional
 Meeting, Pasadena, Calif., Oct. 19-24 (1993b); Alauddin, M. M., et al.,
 "Selective alkylation of pyrimidyl dianions II: Synthesis,
 characterization and comparative reactivity of 3', 5'-o-bis
 tetrahydropyranyl, trimethylsilyl, and t-butyldimethylsilyl derivatives of
 5-bromo-deoxyuridine", Tetrahedron, 50:1699-1706 (1994)}. The synthesis is
 illustrated in FIG. 5.
 ##STR1##
 After purification by flash chromatography compound 2 could be stored at
 room temperature for at least 10 months under anhydrous conditions. Its
 melting point was broad due to the fact that a mixture of four
 diastereomers were probably present. Treatment of compound 2 with
 n-butyllithium (2.5 equivalent) produced the dianion 3 in situ which was
 treated with either unlabeled or [.sup.11 C]-methyl iodide to produce the
 methylated product 4. The major by-product in the methylation reaction was
 the dehalogenated compound 5. The ratio of the desired product to the
 by-product was 43:57, as determined by .sup.1 HNMR integration of the C6
 hydrogen. Deprotection of the tetrahydropyranyl ether produced the desired
 compound FMAU in 82% chemical yield.
 In the radiolabeling experiments a slight modification was made. Briefly, a
 V-vial was used as reaction vessel instead of the round bottom flask used
 in standard preparations. The thick glass of the V-vials required
 additional time to warm the reaction mixture to room temperature (5
 minutes instead of .about.1 minute in the case of regular flask). The
 V-vial containing the in situ generated dianion was connected in series to
 the [.sup.11 C]-methyl iodide apparatus, so that the generated [.sup.11
 C]-methyl iodide could be trapped directly and without delay in the
 reaction vial.
 [.sup.11 C]-Methyl iodide was prepared from [.sup.11 C] CO.sub.2 by a known
 procedure {Marazano, C., et al., "Synthesis of methyl iodide [.sup.11 C]
 and formaldehyde [.sup.11 C].", Int. J. Appl. Rad. IST., 28:49-52 (1977)}.
 Using this procedure approximately 300-325 mCi of .sup.11 C-methyl iodide
 are produced routinely for synthetic work. At this level of .sup.11
 C-methyl iodide, 10-62 mCi of [.sup.11 C]-FMAU could be produced routinely
 with radiochemical yields as high as 53% (based on starting [.sup.11
 C]-methyl iodide) in 30-35 minutes from the end of bombardment.
 Radiochemical purity of [.sup.11 C]-FMAU was routinely&gt;99% with
 specific activity up to 100 Ci/mmole. The major by-product of the reaction
 was the dehalogenated compound 2'-fluoro -1-.beta.-
 D-arabinofuranosyluracil FAU. The labeled FMAU could be separated from FAU
 by HPLC on a reverse phase column using 10% acetonitrile in water as
 eluent. Analysis by HPLC gave peak a (t.sub.r =3.6 min.) which co-elutes
 with an authentic sample of FAU. The second peak b along with a
 radioactive peak (t.sub.r =5.9 min.) elutes at the same retention time as
 the authentic sample of FMAU. The desired product could be separated and
 easily isolated from other radioactive impurities.
 Additional versions of the present invention, which can be used for in vivo
 imaging of cell proliferation, include
 2'-deoxy-2'-fluoro-D-arabinofuranosyl pyrimidine nucleoside analogs having
 .sup.11 C incorporated at positions besides the 5-methyl group of FMAU,
 such as positions within the ring structures of the pyrimidine base.
 Moreover, the imaging agent can be labeled with a positron emitting
 radioisotope other than .sup.11 C, such as .sup.18 F.
 An .sup.18 F-FMAU imaging agent, labeled in the 2' position of the sugar
 molecule, can be prepared based on previously developed procedures for
 synthesizing non-radioactive 2'-deoxy-2'-fluoro-D-arabinofuranosyl
 pyrimidine nucleoside analogs. The synthesis is illustrated in FIG. 6.
 ##STR2##
 1,3,5-tri-O-benzoyl-2-imidazolesulfonyl-.alpha.-D-ribofuranose (8) and
 1,3,5-tri-O-benzoyl-2-fluorosulfonyl-.alpha.-D-ribofuranose (9) can be
 prepared as described in the following references {Chou, T. S., et al.,
 "Triethylamine poly(hydrogen fluorides) in the synthesis of a fluorinated
 nucleoside glycon", Tetrahedron Letters, 37:17-20 (1996); Howell, H. G.,
 et al., "Antiviral nucleosides. A stereospecific, total synthesis of
 2'fluoro-2'deoxy-.beta.-D-arabinofuranosyl nucleosides", J. Org. Chem.,
 53:85-88 (1988); and Tann, C. H., et al., "Fluorocarbohydrates in
 synthesis. An efficient synthesis of
 1-(2-deoxy-2-fluoro-.beta.-D-arabinofuranosyl)thymine (.beta.-FMAU)", J.
 Org. Chem., 50:3644-3647 (1985)}, which are all incorporated herein by
 reference. HF can be substituted with radioactive H.sup.18 F in the
 radiofluorinating agent triethylamine-hydrogen-.sup.18 F-fluoride, which
 is utilized in the step converting compound 9 to
 1,3,5-tri-O-benzoyl-2-deoxy-2fluoro-.beta.-D-arabinofuranose (10). As will
 be apparent to those of skill in the art, other well known
 radiofluorinating agents, such as tetrabutylammonium-.sup.18 F-fluoride
 and tetraethylammonium-.sup.18 F-fluoride, can also be evaluated to
 determine which agent provides the highest radiochemical yield. The
 preparation of 3,5-di-O-benzoyl-2-deoxy-2fluoro-.beta.-D-arabinofuranosyl
 bromide (11) has also been well described in the literature, including the
 above-referenced articles. Moreover, the condensation of 11 and
 2,4-bis-O-(trimethylsilyl)thymine to prepare
 1-(3,5-di-O-benzoyl-2-deoxy-2fluoro- .beta.-D-arabinofuranosyl)thymine
 (12) has been described in Howell, et al., (1988), supra, Tann, et al.
 (1985), supra, and in Niedballa, et al., "A general synthesis of
 N-glycosides. I. Synthesis of pyrimidine nucleosides", J. Org. Chem.,
 39:3654-3663 (1974)} (incorporated herein by reference). In our hands this
 condensation reaction can be conducted in about 15 minutes. The final
 product, 1-(2-deoxy-2-fluoro-.beta.-D-arabinofuranosyl)thymine (FMAU, 13),
 is then prepared by routine basic hydrolysis of compound 12.
 The radiofluorinated sugar 11 prepared in accordance with the present
 invention will allow the synthesis of a number of related nucleoside
 derivatives, depending on the nature of the pyrimidine base being used in
 he condensation reaction. Accordingly, other .sup.18 F-labeled
 2'-deoxy-2'fluoro-D-arabinofuranosyl pyrimidine nucleoside analogs, such
 as [.sup.18 F]FAU, [.sup.18 F]FFAU
 (2'-fluoro-5-fluoro-1-.beta.-D-arabinofuranosyuracil), [.sup.18 F]FIAU and
 [.sup.18 F]FIAC, are considered to be within the scope of the present
 invention.
 The imaging agent of the present invention is used in a manner well known
 in the art for analogous compounds. In general, about 5 mCi up to about 25
 mCi of radiolabeled material in physiological saline solution or
 equivalent vehicle is administered intravenously to a human or animal
 subject prior to imaging or probe studies. Data collection following
 administration may involve dynamic or static techniques with a variety of
 imaging devices, including PET cameras, gamma or SPECT (single photon
 emission computed tomography) cameras with either high energy collimators
 or coincidence detection capabilities, and probe devices designed to
 measure radioactive counts over specific regions of interest.
 The invention may be better understood with reference to the accompanying
 examples, which are intended for purposes of illustration only and should
 not be construed as in any sense limiting the scope of the invention as
 defined in the claims appended hereto.
 EXAMPLE 1
 2'-Fluoro-5-iodo-1-.beta.-D-arabinofuranosyluracil (FIAU),
 2'-fluoro-5-methyl-1-.beta.-D-arabinofuranosyluracil (FMAU), and
 2'-fluoro-1-.beta.-D-arabinofuranosyl-uracil (FAU) were prepared according
 to published procedures {Watanabe, K. A., et al., "Nucleosides. 110.
 Synthesis and anitherpes virus activity of some
 2'-fluoro-2'-deoxyarabinofuranosylpyrimidine Nucleosides", J. Med. Chem.,
 22:21-24 (1979)}. p-Toluenesulfonic acid, 2,3-dihydropyran, and
 n-butyllithium were purchased from Aldrich. Flash chromatography was
 performed using silica gel 60 (E. M. Science) and HPLC grade solvents.
 Thin layer chromatography (TLC) was performed on pre-coated Kieselgel 60
 F254 (Merck) glass plates. Melting points were determined on a capillary
 melting point apparatus and are uncorrected. .sup.1 HNMR studies were
 performed on a Bruker AMX300 spectrometer using tetramethylsilane as
 internal reference, unless otherwise specified. Mass spectra were obtained
 on a Finnigan 4000 mass spectrometer using ammonia chemical ionization
 technique unless otherwise specified, and m/z are reported only on the
 major peaks with relative intensity in the parenthesis. High performance
 liquid chromatography (HPLC) was performed on a Waters HPLC single pump
 isocratic system equipped with a computer (Macintosh), a UV detector
 (ISCO) at 254 nm, a radioactive detector (Technical Associates), and a
 semipreparative reverse phase C.sub.18 column (Econosil, 10 micron, 250
 mm.times.10 mm; Alltech). A solvent system of 10% acetonitrile in water
 was used as mobile phase.
 For preparation of [.sup.11 C]-methyl iodide, [.sup.11 C]-CO.sub.2 was
 produced by the reaction .sup.14 N (p, .alpha.) .sup.11 C in a RDS-112
 Siemens 11 MeV cyclotron following a known procedure {Marazano, et al.
 (1977), supra}. Briefly, [.sup.11 C]-CO.sub.2 was bubbled through a
 solution of LiAIH.sub.4 in THF (.about.300 .mu.L, 8-10 mg/mL) under argon.
 The solvent was evaporated, and the residue was treated with HI
 (.about.0.5 mL). The reaction mixture was heated under reflux for 2
 minutes. The [.sup.11 C]-methyl iodide produced was passed through columns
 of P.sub.2 O.sub.5 /NaOH, and finally bubbled through the pre-cooled
 solution of the dianion 3 in THF at -78.degree. C.
 For preparation of 3',
 5'-O-bis-(tetrahydropyranyl)-2'-fluoro-5-iodo-1-.beta.-D-arabino-furanosyl
 uracil (2), 2'-Fluoro-5-iodo-1-.beta.-D-arabinofuranosyluracil (FIAU, 1)
 (71 mg, 0.19 mmol) was dissolved in dry THF (2 mL). p-Toluenesulfonic acid
 (catalytic amount) was added to the reaction flask followed by addition of
 2,3-dihydropyran (0.242 mL, 2.8 mmol). The reaction mixture was stirred at
 room temperature for 2 h, at which time TLC showed no remaining starting
 material. The reaction was quenched by adding 2 drops of triethylamine.
 The solvent was evaporated, and the crude product was purified by flash
 chromatography using a silica gel column and 25% acetone in hexane as
 eluent. White solid, 96 mg of compound was obtained as a diastereomeric
 mixture in 93% yield. M.P. 65-76.degree. C. .sup.1 HNMR (CDCl.sup.3):
 8.748 (bs, 1H, NH), 8.019-7.974 (s, 1H, C.sub.6 H), 6.260-6.149 (dd, 1H,
 1'H), 5.240 and 5.066 (2dd, 1H, 2'H, J FH=51.24 Hz, J HH=2.7 Hz),
 4.805-4.726 (m, 2H), 4.255-3.565 (m, 9H), 1.834-1.570 (m, 11H). MS: 558
 (M+NH.sub.4, 4), 541 (M+1, 2), 474 (21), 415 (16), 348 (62), 331 (100),
 264 (35), 118 (24). Exact mass calculated for 2:540.0768; found: 540.0782
 by isobutane chemical ionization MS.
 For preparation of 3',
 5'-O-bis-(tetrahydropyranyl)-2'-fluoro-5-methyl-1-.beta.-D-arabinofuranosy
 luracil (4), 3',
 5'-O-Bis-(tetrahydropyranyl)-2'-fluoro-1-.beta.-D-arabinofuranosyluracil
 (20 mg, 0.037 mmol) was dissolved in dry THF (1 mL) under argon and cooled
 to -78.degree. C. n-Butyllithium (1.6M soln in hexane, 0.06 mL, 0.092
 mmol) was injected into the cold solution, and the reaction mixture was
 stirred for 30 seconds. Methyl iodide (0.010 mL, 0.16 mmol) was injected
 into the reaction mixture, stirred for one minute, after which the cold
 bath was removed. By 2 minutes following addition of methyl iodide, no
 starting material was identified on TLC. The reaction was quenched with
 0.10 mL saturated ammonium chloride solution and warmed to room
 temperature. Ethyl acetate (7 mL) was added to the reaction mixture, and
 the resulting solution was washed first with water (2.times.8 mL) and then
 with brine (1.times.5 mL). The aqueous phase was back extracted with ethyl
 acetate (1.times.8 mL). The combined organic phase was dried (Na.sub.2
 SO.sub.4) and evaporated to produce 16 mg of crude product. .sup.1 HNMR of
 this crude product showed a mixture of two compounds in the ratio 43:57
 obtained by integration of the C.sub.6 protons. The crude product was
 chromatographed using silica gel column and 20% acetone in hexane as
 eluent to produce 4 mg (25% yield) of the desired product. .sup.1 HNMR
 (CDCl.sub.3): 8.217 (bs, 1H, NH), 7.408 and 7.373 (2s, 1H, C.sub.6 H),
 6.260-6.181 (dd, 1H, 1'H), 5.209 and 5.031 (2d, 1H, 2'H, J FH=52.8 Hz),
 4.802 -4.711 (m, 2H), 4.486-3.543 (m, 9H), 1.918 (s, 3H, CH.sub.3),
 1.790-1.573 (m, 11H). MS: 429 (M+1, 11), 362 (19), 345 (100), 261 (20),
 118 (7). 3',
 5'-O-bis-(tetrahydropyranyl)-2'-fluoro-1-.beta.-D-arabinofuranosyluracil
 (5) was isolated as a by-product from the alkylation of the THP-protected
 FIAU described above. It gave acceptable spectra.
 For preparation of 2'-fluoro-5-methyl-1-.beta.-D-arabinofuranosyluracil
 (FMAU, 6), 3',
 5'-O-Bis-(tetrahydropyranyl)-5-methyl-1-.beta.-D-arabinofuranosyluracil (4
 mg, 0.0093 mmol) was dissolved in methanol (1 mL) and three drops of
 methanol/conc. HCl (9:2) were added. The reaction mixture was refluxed for
 3 minutes, when TLC showed no starting material remaining. The solvent was
 evaporated, the residue was washed with hexane and the washing was
 discarded. After evaporating off the residual solvent, 2 mg of the desired
 product was obtained in 82% yield. .sup.1 HNMR (D.sub.2 O): 7.656 (s, 1H,
 C.sub.6 H), 6.265 (dd, 1H, 1'H, J FH=16.86 Hz, J HH=4 Hz), 5.200 (dt, 1H,
 2'H, J FH=51.6 Hz, J HH=3 Hz), 4.431 (dt, 1H, 3'H, J FH=19.7 Hz, J HH=2.8
 Hz), 4.029 (q, 1H, 4'H, J=3.7 Hz), 3.959-3.823 (m, 2H, 5'H), 1.894 (s, 3H,
 CH.sub.3). MS (FAB): 261 (M+1).
 Preparation of 2'-fluoro-5-[.sup.11
 C-methyl]-1-.beta.-D-arabinofuranosyluracil ([.sup.11 C]-FMAU) was carried
 out as follows. 3',
 5'-o-Bis-(tetrahydropyranyl)-2'-fluoro-1-.beta.-D-arabinofuranosyluracil 2
 (10 mg, 0.0185 mmol) was dissolved in dry THF (0.5 mL) in a V-vial under
 argon and cooled to -78.degree. C. n-Butyllithium (1.6M soln in hexane,
 0.035 mL, 0.046 mmol) was injected into the cold solution. [.sup.11
 C]-Methyl iodide was bubbled into the reaction mixture for 2 minutes.
 Trapped activity was measured in a dose calibrator (Capintec). The
 reaction mixture was warmed to room temperature followed by addition of 2M
 HCl in methanol (120 .mu.L). The mixture was heated to reflux for 3
 minutes in a heating block at 110.degree. C. The residual solvent was
 evaporated with argon for 1 minute. After cooling, the reaction mixture
 was neutralized with 2M NaOH solution (80 .mu.L). The crude product was
 diluted with HPLC solvent (1 mL), and injected onto the semipreparative
 HPLC column for purification. The desired product was isolated from the
 appropriate fraction. Quality control was performed by injecting an
 aliquot onto the HPLC column.
 HPLC analysis of [.sup.11 C]-FMAU and FAU was carried out as follows. FAU
 was eluted at 6.2 minutes and [.sup.11 C]-FMAU was eluted at 9.7 minutes
 at a flow rate of 4 mL/minute. Isolated product was re-analyzed on the
 same column using a flow rate of 6 mL/min (t.sub.r =5.9 min).
 EXAMPLE 2
 The following experiments using a canine brain tumor model, show that
 [.sup.11 C]FMAU is an unexpectedly effective in vivo imaging agent for
 detecting proliferating cells in uninfected subjects. [.sup.11 C]FMAU
 localized selectively within the proliferating cells of brain tumors, but
 not in normal brain cells. In contrast, the nucleoside analog [.sup.11
 C]TdR did not localize selectively enough to give a clear image of the
 tumor
 The experiments compared [.sup.11 C]FMAU with [.sup.11 C]TdR in dogs before
 and after implantation of gliosarcoma. The dogs were not infected by
 herpes simplex virus. A bolus containing about 20-25 mCi of [.sup.11
 C]FMAU or [.sup.11 C]TdR, having a specific activity of about 50-100
 Ci/mmol was injected intravenously. Like TdR, FMAU demonstrated rapid
 plasma clearance. FIG. 1 shows the plasma activity concentration curve for
 FMAU, which decayed as two exponential components having approximately
 equal amplitudes and half times of 2.4 and 63 minutes.
 HPLC analysis of plasma samples demonstrated no radiolabeled metabolites of
 FMAU over 90 minutes. As shown in the PET scans of FIG. 2B and FIG. 3,
 virtually no radioactivity was observed in normal brain following
 administration of FMAU. This is very different from TdR, which a showed a
 progressive rise in radiolabeled metabolites, which were able to cross the
 blood-brain barrier and accumulate within the normal brain (see Exhibit
 2A). This confirmation of lack of short-term catabolism and
 pharmacokinetics of [.sup.11 C]FMAU was essential in determining the
 utility of this agent for imaging, given the rapid breakdown of the parent
 compound TdR and the associated imaging problems in the canine model, see
 e.g., Exhibit 2 (A and C). No such information was ever published
 previously.
 Compared to [.sup.11 C]TdR, the tumor was well visualized using [.sup.11
 C]FMAU, see e.g., Exhibits 2D and 3. Unlike previous studies, which used
 [.sup.14 C] FMAU for autoradiographic detection of virus-infected cells,
 [.sup.11 C]FMAU accumulated within brain tumor cells that were not
 infected with herpes simplex virus. These results are summarized in FIG. 4
 (A and B), which shows that 60 minutes after administering the imaging
 agents, the tumor-to-contralateral ratio was about 4.3:1 for FMAU versus
 1.4:1 for TdR. Clearly, TdR was markedly less effective at imaging
 proliferating cells in vivo than FMAU. This result was unexpected because
 TdR uptake is commonly used for measuring cell proliferation in vitro and
 for tumor imaging in vivo. These experiments demonstrate that [.sup.11
 C]FMAU is an unexpectedly superior in vivo imaging agent for detecting
 cell proliferation, rather than viral infection. In addition, we have
 shown that an appropriate dose for in vivo imaging is about 20-25 mCi of
 [.sup.11 C]FMAU having a specific activity of about 50-100 Ci/mmol.
 From the foregoing description, one skilled in the art can readily
 ascertain the essential characteristics of the invention and, without
 departing from the spirit and scope thereof, can adapt the invention to
 various usages and conditions. Changes in form and substitution of
 equivalents are contemplated as circumstances may suggest or render
 expedient, and although specific terms have been employed herein, they are
 intended in a descriptive sense and not for purposes of limitation.