Abstract:
The invention provides novel amino acid compounds of use in detecting and evaluating brain and body tumors. These compounds combine the advantageous properties of 1-amino-cycloalkyl-1-carboxylic acids, namely, their rapid uptake and prolonged retention in tumors with the properties of halogen substituents, including certain useful halogen isotopes including fluorine-18, iodine-123, iodine-125, iodine-131, bromine-75, bromine-76, bromine-77 and bromine-82. In one aspect, the invention features amino acid compounds that have a high specificity for target sites when administered to a subject in vivo. Preferred amino acid compounds show a target to non-target ratio of at least 5:1, are stable in vivo and substantially localized to target within 1 hour after administration. An especially preferred amino acid compound is   18  F!-1-amino-3-fluorocyclobutane-1-carboxylic acid (FACBC). In another aspect, the invention features pharmaceutical compositions comprised of an α-amino acid moiety attached to either a four, five, or a six member carbon-chain ring. In addition, the invention features analogs of α-aminoisobutyric acid.

Description:
The U.S. Government has certain rights in this invention, based upon partial support provided by Department of Energy Grant No. DE-FG05-93ER61737. 
    
    
     This is a continuation-in-part of U.S. application Ser. No. 08/554,906, filed Nov. 9, 1995, from which priority is claimed. 
    
    
     FIELD OF THE INVENTION 
     The invention includes novel chemical compounds having specific binding in a biological system and capable of being used for positron emission tomography (PET) and single photon emission (SPECT) imaging methods. 
     BACKGROUND OF THE INVENTION 
     The ability of analog compounds to bind to localized ligands within the body would make it possible, in principle, to utilize such compounds for in situ imaging of the ligands by PET, SPECT and similar imaging methods. In principle, nothing need be known about the nature of the ligand, as long as binding occurs, and such binding is specific for a class of cells, organs, tissues or receptors of interest. PET imaging is accomplished with the aid of tracer compounds labeled with a positron-emitting isotope (Goodman, M. M. Clinical Positron Emission Tomography, Mosby Yearbook, 1992, K. F. Hubner et al., Chapter 14). For most biological materials, suitable isotopes are few. The carbon isotope,  11  C!, has been used for PET, but its short half-life of 20.5 minutes limits its usefulness to compounds that can be synthesized and purified quickly, and to facilities that are proximate to a cyclotron where the precursor   11  C! starting material is generated. Other isotopes have even shorter half-lives.   13  N! has a half-life of 10 minutes and   15  O! has an even shorter half-life of 2 minutes. The emissions of both are more energetic than those of   11  C!. Nevertheless, PET studies have been carried out with these isotopes (Hubner, K. F., in Clinical Positron Emission Tomography, Mosby Year Book, 1992, K. F. Hubner, et al., Chapter 2). A more useful isotope,  18  F!, has a half-life of 110 minutes. This allows sufficient time for incorporation into a radio-labeled tracer, for purification and for administration into a human or animal subject. In addition, facilities more remote from a cyclotron, up to about a 200 mile radius, can make use of   18  F! labeled compounds. Disadvantages of   18  F! are the relative scarcity of fluorinated analogs that have functional equivalence to naturally-occurring biological materials, and the difficulty of designing methods of synthesis that efficiently utilize the starting material generated in the cyclotron. Such starting material can be either fluoride ion or fluorine gas. In the latter case only one fluorine atom of the bimolecular gas is actually a radionuclide, so the gas is designated  18  F-F. Reactions using  18  F-F as starting material therefore yield products having only one half the radionuclide abundance of reactions utilizing K 18  F as starting material. On the other hand,   18  F! can be prepared in curie quantities as fluoride ion for incorporation into a radiopharmaceutical compound in high specific activity, theoretically 1.7 Ci/nmol using carrier-free nucleophilic substitution reactions. The energy emission of   18  F! is 0.635 MeV, resulting in a relatively short, 2.4 mm average positron range in tissue, permitting high resolution PET images. 
     SPECT imaging employs isotope tracers that emit high energy photons (γ-emitters). The range of useful isotopes is greater than for PET, but SPECT provides lower three-dimensional resolution. Nevertheless, SPECT is widely used to obtain clinically significant information about analog binding, localization and clearance rates. A useful isotope for SPECT imaging is   123  I!, a γ-emitter with a 13.3 hour half life. Compounds labeled with   123  I! can be shipped up to about 1000 miles from the manufacturing site, or the isotope itself can be transported for on-site synthesis. Eighty-five percent of the isotope&#39;s emissions are 159 KeV photons, which is readily measured by SPECT instrumentation currently in use. 
     Use of   18  F! labeled compounds in PET has been limited to a few analog compounds. Most notably,   18  F!-fluorodeoxyglucose has been widely used in studies of glucose metabolism and localization of glucose uptake associated with brain activity.   18  F!-L-fluorodopa and other dopamine receptor analogs have also been used in mapping dopamine receptor distribution. 
     Other halogen isotopes can serve for PET or SPECT imaging, or for conventional tracer labelling. These include  75  Br,  76  Br,  77  Br and  82  Br as having usable half-lives and emission characteristics. In general, the chemical means exist to substitute any halogen moiety for the described isotopes. Therefore, the biochemical or physiological activities of any halogenated homolog of the described compounds are now available for use by those skilled in the art, including stable isotope halogen homologs. Astatine can be substituted for other halogen isotopes,   210  At! for example emits alpha particles with a half-life of 8.3h. Other isotopes also emit alpha particles with reasonably useful half-lives. At-substituted compounds are therefore useful for tumor therapy, where binding is sufficiently tumor-specific. 
     Numerous studies have demonstrated increased incorporation of carbohydrates and amino acids into malignant tumor cells. This accumulation is associated with accelerated proliferation and protein synthesis of such cells. The glucose analog   18  F!-2-fluoro-2-deoxy-D-glucose (2-FDG) has been used for distinguishing highly malignant brain tumors from normal brain tissue or benign growths (DiChiro, G. et al. (1982) Neurology (NY) 32:1323-1329. However, fluorine-18 labeled 2-FDG is not the agent of choice for detecting low grade brain tumors because high uptake in normal tissue can mask the presence of a tumor. In addition, fluorine-18 labeled 2-FDG is not the ideal radiopharmaceutical for distinguishing lung tumors from infectious tissue or detecting ovarian carcinoma because of high uptake of the 2-FDG radioactivity in infectious tissue and in the bladder, respectively. The naturally occurring amino acid methionine, labeled with carbon-11, has also been used to distinguish malignant tissue from normal tissue. But it too has relatively high uptake in normal tissue. Moreover, the half-life of carbon-11 is only 20 minutes, therefore   11  C! methionine can not be stored for a long period of time. 
     In an article titled, &#34;1-Aminocyclobutane  11  C!carboxylic Acid, a Potential Tumor-Seeking Agent,&#34; published in J. Nucl. Med.20:1055-1061 (1979), L. C. Washburn et al. reported that the unnatural, alicyclic α-amino acid, 1-aminocyclobutanecarboxylic acid (ACBC), labeled with carbon-14 or carbon-11, was incorporated preferentially by several tumor types in animals. ACBC has been shown to be a selective substrate for protein synthesis in metastatic lesions in the brain with little observable uptake in normal brain tissue. 
     1-Amino-1-cyclobutane carboxylic acid is also a selective and potent ligand and antagonist for the excitatory amino acid receptor subtype N-methyl-D-aspartic acid (NMDA), specifically the strychnine-insensitive glycine recognition site. The NMDA receptor has been implicated in CNS disorders such as epilepsy, stroke, Huntington&#39;s disease, Alzheimer&#39;s disease and schizophrenia. 
     Synthesis of ACBC has been carried out by the well-known Bucherer-Streker synthesis which is suitable for labeling with   11  C! using   11  C!-cyanide as precursor. (Washburn, L. C. et al., in Radiopharmaceuticals II: Proceedings 2nd International Symposium on Radiopharmaceuticals, Mar. 19-22, 1979, Seattle, Wash.) 
     SUMMARY OF THE INVENTION 
     The invention provides novel amino acid compounds of use in detecting and evaluating brain and body tumors. These compounds combine the advantageous properties of 1-amino-cycloalkyl-1-carboxylic acids, namely, their rapid uptake and prolonged retention in tumors with the properties of halogen substituents, including certain useful halogen isotopes including fluorine-18, iodine-123, iodine-125, iodine-131, bromine-75, bromine-76, bromine-77, bromine-82, astatine-210, astatine-211, and other astatine isotopes. 
     In one aspect, the invention features amino acid compounds that have a high specificity for target sites when administered to a subject in vivo. Preferred amino acid compounds show a target to non-target ratio of at least 5:1, are stable in vivo and substantially localized to target within 1 hour after administration. An especially preferred amino acid compound is   18  F!-1-amino-3-fluorocyclobutane-1-carboxylic acid (FACBC). 
     In another aspect, the invention features pharmaceutical compositions comprised of an α-amino acid moiety attached to either a four, five, or a six member carbon-chain ring. In addition, the invention features analogs of α-aminoisobutyric acid. 
     In a further aspect, the invention features amino acid compounds further comprising an imaging agent and uses for the compounds in detecting and/or monitoring tumors in a subject. In one embodiment, the amino acid compound imaging agent is administered in vivo and monitored using a means appropriate for the label. Preferred methods for detecting and/or monitoring an amino acid compound imaging agent in vivo include Positron Emission Tomography (PET) and Single Photon Emission Computer Tomography (SPECT). 
     Compounds of the invention include fluoro-, bromo- or iodo-substituted cyclobutyl, cyclopentyl, cyclohexyl amino acids as shown in Scheme 1 or singly unsaturated cyclic homologs thereof as shown in Scheme 2, or methylenyl fluoride or iodide-substituted analogs, as shown in Scheme 3, or fluoro- or iodo-substituted isobutyl amino acids as shown in Scheme 4. The substituted cyclic compounds of Schemes 1--3 belong to the following generic formula: ##STR1## where R 1  is X, X--CH═CH--, or R 3  R 2  is H, or R 3  if R 1  is R 3 , ##STR2## is formed where 
     x is 0 or 1, 
     y is 1 or 2, 
     z is 1, 2, 3 or 4 and z&gt;y if y is 2, 
     q is 1 or 0 if n is 1 and j is 0, 
     n is 1 or 2, but 0 if m is 0, 
     m is 0 or 1, 
     j is 0 or 1, and 
     X is F,  18  F, I,  123  I,  125  I,  131  I, Br,  75  Br,  76  Br,  77  Br,  82  Br, or At 
     Non-cyclic, but sterically similar compounds of the invention have the following generic formula, as shown in Scheme 4. ##STR3## where R 1 , is X or X--CH═CH-- 
     and X is I,  131  I,  123  I,  125  I , F,  18  F, Br,  75  Br ,  76  Br,  77  Br,  82  Br, or At 
     The compounds of the invention are useful as tumor-binding agents and as NMDA receptor-binding ligands, and in radio-isotopic form are especially useful as tracer compounds for tumor imaging techniques, including PET and SPECT imaging. Where X is At, the compounds have utility for radio-therapy. In order to synthesize the compounds to maximize a useful lifetime for short-lived isotopes, and to maximize yield and purity, specialized, non-standard routes had to be devised, as described. 
     The compounds of the invention can be labeled with Technetium. Technetium-99m is known to be a useful radionuclide for SPECT imaging. The cyclic amino acids of the invention are joined to a Tc-99m metal cluster through a 4-6 carbon chain which can be saturated or possess a double or triple bond. The Tc-99m metal cluster can be, for example, an alkylthiolato complex, a cytectrene or a hydrazino nicotinamide complex (HYNIC). The linking structure can be R 4  (replacing R 3 ) in the foregoing diagram where R 4  is Z--(CH 2 ) a  --CH b  --CH b  --CH&lt; where a is 1, 2 or 3, b is 0, 1 or 2, and Z is an alkylthiolato-Te complex, a Tc-cytectrene or a Tc-HYNIC complex. ##STR4## 
     DETAILED DESCRIPTION OF THE INVENTION 
     Compounds of the invention provide substantially improved PET imaging for areas of the body having malignant tumors, especially tumors of the brain. All the available positron-emitting isotopes which could be incorporated into a biologically-active compound have short half-lives. The practical utility of such labeled compounds is therefore dependent on how rapidly the labeled compound can be synthesized, the synthetic yield and the radiochemical purity of the final product. Even the shipping time from the isotope source, a cyclotron facility, to the hospital or laboratory where PET imaging is to take place, is limited. A rough calculation of the useful distance is about two miles per minute of half-life. Thus   11  C!, with a half-life of 20.5m is restricted to about a 40 mile radius from a source whereas compounds labeled with   18  F! can be used within about a 200 mile radius. Further requirements of an   18  F!-labeled compound are that it have the binding specificity for the receptor or target molecule it is intended to bind, that non-specific binding to other targets be sufficiently low to permit distinguishing between target and non-target binding, and that the label be stable under conditions of the test to avoid exchange with other substances in the test environment. More particularly, compounds of the invention must display adequate binding to the desired target while failing to bind to any comparable degree with other tissues or cells. Furthermore, the fluorine, iodine or bromine label must not be labile or unstable such that significant amounts appear in, e.g. bone or thyroid, or other non-taret tissue respectively. 
     A partial solution to the stringent requirements for PET imaging is to employ γ-emitting isotopes in SPECT imaging.   123  I! is a commonly used isotopic marker for SPECT, having a half-life of 13 hours for a useful range of over 1000 miles from the site of synthesis. Compounds of the invention can be rapidly and efficiently labeled with   123  I! for use in SPECT analysis as an alternative to PET imaging. Furthermore, because of the fact that the same compound can be labeled with either isotope, it is possible for the first time to compare the results obtained by PET and SPECT using the same tracer. 
     In vivo distribution of a compound of the invention,   18  F!-1-amino-3-fluoro-cyclobutane-1-carboxylic acid (FACBC) was measured in rats having an implanted gliosarcoma. Accumulation in various tissue was measured at 5 min and 60 min post-administration. The compound was immediately seen to be preferentially associated with tumor tissue as early as 5 minutes post administration, with relatively little uptake in other tissues. After 60 minutes, an increased level of tumor uptake relative to non-malignant brain tissue was observed, with very little additional uptake in other tissues. Uptake by bone was essentially constant over the 60 minutes of exposure, indicating stability of the 2-cyclobutyl group to significant in vivo defluorination. The tumor uptake exhibited a maximum at 60 minutes of 1.72% of total injected dose/gram of tissue, with a maximum ratio of tumor to brain of 6.61, compared to 5.58 at 5 minutes. By contrast,   18  F! fluorodeoxyglycose (FDG) showed rapid accumulation but poor discrimination between tumor and brain, the dose/gram ratio of tumor uptake to brain uptake being 0.84 at 60 min. The results with   18  F! FACBC indicate that the compound is a valuable imaging agent for diagnosis, management and imaging of malignant tumors, using PET imaging. 
     The specificity of tumor binding also provides utility for I-substituted compounds of the invention. Such compounds can be labeled with short-lived  123  I for SPECT imaging or with longer-lived  1251  I for longer-term studies such as monitoring a course of therapy. Other iodine and bromine isotopes can be substituted for those exemplified. 
     The compounds of the invention therefore provide improved methods for tumor imaging using PET and SPECT. The methods entail administering to a subject (which can be human or animal, for experimental and/or diagnostic purposes) an image-generating amount of a compound of the invention, labeled with the appropriate isotope and then measuring the distribution of the compound by PET if   18  F! or other positron emitter is employed, or SPECT if   123  I! or other gamma emitter is employed. An image-generating amount is that amount which is at least able to provide an image in a PET or SPECT scanner, taking into account the scanner&#39;s detection sensitivity and noise level, the age of the isotope, the body size of the subject and route of administration, all such variables being exemplary of those known and accounted for by calculations and measurements known to those skilled in the art without resort to undue experimentation. 
     It will be understood that compounds of the invention can be labeled with an isotope of any atom or combination of atoms in the structure. While   18  F!,   123  I! and   125  I! have been emphasized herein as being particularly useful for PET, SPECT and tracer analysis, other uses are contemplated including those flowing from physiological or pharmacological properties of stable isotope homologs and will be apparent to those skilled in the art. 
     A high degree of tumor specific binding has been observed for compounds of the invention, in human patients as well as in experimental animals. The high specificity has inspired the use of At-substituted compounds of the invention for therapeutic use. At isotopes are emitters of alpha particles, where short range is useful for tumor radiotherapy. 
    
    
     The invention also provides for technetium (Tc) labeling via Tc adducts. Isotopes of Tc, notably Tc 99m , have been used for tumor imaging. The present invention provides Tc-complexed adducts of compounds of the invention, which are useful for tumor imaging. The adducts are Tc-coordination complexes joined to the cyclic amino acid by a 4-6 carbon chain which can be saturated or possess a double or triple bond. Where a double bond is present, either E (trans) or Z (cis) isomers can be synthesized, and either isomer can be employed. Synthesis is described for incorporating the  99m  Tc isotope as a last step, to maximize the useful life of the isotope. 
     EXAMPLE 1 
     Synthesis of  18F!1-amino-3-fluorocyclobutane-1-carboxylic acid (FACBC) 
     As will be described in detail hereinafter, the compound can be prepared by the steps represented in Steps 1-11. 
     The following methods were employed in procedures reported herein.   18  F!-Fluoride was produced from a Seimens cyclotron using the  18  O(p,n) 18  F reaction with 11 MeV protons on 95% enriched   18  O! water. All solvents and chemicals were analytical grade and were used without further purification. Melting points of compounds were determined in capillary tubes by using a Buchi SP apparatus. Thin-layer chromatographic analysis (TLC) was performed by using 250-mm thick layers of silica gel G PF-254 coated on aluminum (obtained from Analtech, Inc.). Column chromatography was performed by using 60-200 mesh silica gel (Aldrich Co.). Infrared spectra (IR) were recorded on a Beckman 18A spectrophotometer with NaCl plates. Proton nuclear magnetic resonance spectra (1H NMR) were obtained at 300 MHz with a Nicolet high-resolution instrument. 
     Synthesis of 1-Chloro-2-benzyloxy-3-bromopropane 3 
     A mixture of benzyl bromide 1 (46.2 g, 0.27 mol), epichlorohydrin 2 (25 g, 0.27 mol), and 0.045 g of mercurous chloride was heated for 12 hr at 150° C. (Step 1). Distillation through a 12-in Vigreux column yielded 55.8 g (79%) of 1-chloro-2-benzyloxy-3-bromopropane, 3 bp 142-145 (0.3 mm); 1H NMR (CDCl 3 ) δ3.34-3.9 (m,4H, CH 2 ), 4.58 (s,2H,O--CH 2 ), 7.26 (s, 5H, phenyl). 
     Synthesis of Diethyl-3-benzyloxy cyclobutane-1-dicarboxylate 4 
     To a stirred slurry of 4.6 g (0.19 mol) sodium hydride in 115 mL of dry dioxane was added dropwise 30.4 (0.10 mol) of diethyl malonate over a 30 min period. After this addition was complete, 50.0 g (0.19 mol) of 1-chloro-2-benzyloxy-3-bromopropane 3 was added dropwise in 30 min (St mixture was heated at reflux for 44 hr, cooled to room ##STR5## temperature, and 4.6 g (0.19 mol) of sodium hydride in 50 mL of dioxane was added in portions. The mixture was heated at reflux for an additional 120 hr. The solvent was partially removed under reduced pressure and the mixture was treated with 100 mL of water. The organic layer was extracted into ether. The ether extracts were dried and concentrated and the residue was distilled under reduced pressure. Distillation through a 12-in Vigreux column yielded 49.0 g (85%) of diethyl 3-benzyloxycyclobutane-1, 1-dicarboxylate 4 bp 174°-176° C. (0.9 mm);  1  H NMR(CDCl 3 ) δ1.23 (t, J=7 Hz, 6H, CH 3 ), 4.0-4.7 (m, 1H OCH), 4.34 (s, 2H OCH 2 ), 4.13 (q, J=7 Hz, 4H, OCOCH 2 ), 7.23 (s, 5H, phenyl). 
     Synthesis of 3-benzyloxycyclobutane-1,1-dicarboxamine 5 
     Diethyl 3-benzyloxycyclobutane-1,1-dicarboxylate 4 (20 g. 65mmol) was stirred with concentrated aqueous ammonia (250 mL) for four days at room temperature (Step 3). The diamide 5 was collected by filtration and washed with water followed by ethyl acetate. The yield was 8.1 g (50%).  1  H NMR (d6-DMSO) δ2.2 (m, 2H, CH 2 ), 2.5 (m, 2H, CH 2 ), 3.8 (q, J=7.2 Hz 1H OCH), 4.3 (s, 2H, OCH 2 ), 7.0 (m, 4H, NH 2 ), 7.23 (s, 5H, phenyl). 
     Synthesis of cis/trans 5-(3-benzyloxycyclobutane)hydantoin 6 
     3-Benzyloxycyclobutane-1, 1-dicarboxamine, 5 (2.0 g, 8 mmol) was stirred in 150 mL of dilute sodium hypochlorite (Aldrich product/water 1 to 2) at 0°-5° C. for four hrs (Step 4). The reaction mixture stood overnight at room temperature. Unreacted diamide was recovered by filtration. The solution was neutralized to pH 5 with concentrated hydrochloric acid and evaporated to dryness in vacuo. The residue was extracted with 50 mL of hot methanol, filtered, and washed with 50 mL of hot methanol. The methanol solutions were combined and evaporated. Yield of the mixture of cis and trans hydantoins 6 was 1.4 g(70%). 
     Synthesis of 1-amino-3-benzyloxycyclobutane-1-carboxylic acid 7 
     The hydantoin 6 (1.0 g,4.1 mmol) was hydrolyzed by refluxing with 10 mL of a barium hydroxide solution (saturated at room temperature) for 16 hr (Step 5). The solution was neutralized to pH 6 with 2M sulfuric acid and evaporated to dryness in vacuo. The residue was extracted with 50 mL of hot methanol, filtered, and washed with 50 mL of hot methanol. The methanol solutions were combined and evaporated. Yield of the 1-amino-3-benzyloxycyclobutane-1-carboxylic acid 7 was 0.69 g(76%).  1  H NMR (d 4  -methanol) δ2.2-2.9 (m, 4H, CH 2 ), 4.3 (t, J=6.9 Hz, 1H, OCH), 4.5 (s, 2H, OCH 2 ), 7.23 (br s, 5H, phenyl). 
     Synthesis of 1-t-butylcarbamate-3-benzyloxycyclobutane-1-carboxylic acid 8 
     A solution of the amino acid 7 (0.5 g, 2.3 mmol) in 10 mL of a mixture of methanol/triethylamine (90:10) was treated with 1.0 g (4.6 mmol) of di-tert-butyldicarbonate (Step 6). The mixture was heated at 50°-60° C. for 10 min and then the solvent was removed by rotoevaporation. The crude product was stirred in 5 mL of dilute HCl (pH=2) at 0° C. for 10 min. The mixture was extracted with CH 2  Cl 2  (2×10 mL), the combined extract dried, and the solvent was removed. The crude oil was chromatographed on silica gel using methylene chloride/methanol (9 to 1) with 0.1% formic acid. The product 8 (0.55 g, 78%) showed a single spot on TLC (Rf=0.59) with the same solvent system; visualization was with MoO.H 3  PO 4 . 
     Synthesis of 1-t-butylcarbamate-3-benzyloxycyclobutane-1-carboxylic-methyl ester 9 
     To a slurry of 1-methyl-3-nitro-1-nitrosoguandine (150 mg) in 8 mL of ether at 0°-5° C. was added a 40% solution of potassium hydroxide dropwise. The resultant diazomethane ether solution was added to 0.15 g(0.50 mmol) of 1-t-butyl carbamate-3-benzyloxycyclobutane-1-carboxylic methyl ester acid in 3 mL of ether (Step 7) and the mixture was stirred at room temperature for 15 min. The mixture was washed with water (10 mL) and the ether evaporated. The crude residue was chromatographed on silica gel using ethyl acetate/hexane (1 to 9). Yield: 0.13 g (82%);  1  H NMR (CDCl 3 ) δ1.35 (s, 9H, CH 3 ), 2.27-2.88 (m, 4H, CH 2 ), 3.72 (s, 3H, CH 3 ) 4.18 (m, 1H, CHO), 4.42 (s, 2H, OCH 2 ), 7.23 (br s, 5H, phenyl). cl Synthesis of 1-t-butylcarbamate-3-hydroxy-cyclobutane-1-carboxylic acid methyl ester 10 
     A solution of 0.10 g (0.3 mmol) of the protected amino acid benzyl ether 9 in 5 mL of methanol was mixed with a suspension of 25 mg of 10% palladium on charcoal in 5 mL of methanol (Step 8). The mixture was stirred under a positive pressure of hydrogen (balloon) for 16 hr. The catalyst was filtered off and the solvent was evaporated. The crude residue was chromatographed on silica gel using methylene chloride/methanol (9 to 1). The product 10(74 mg 89%) showed a single spot on TLC (Rf=0.81) with the same solvent system; visualization was with MoO.H 3  PO 4 . 
     Synthesis of 1-t-butylcarbamate-3-trifluoromethane sulfonoxycyclobutane-1-carboxylic acid methyl ester 11 
     The alcohol 10(25 mg, 0.10 mmol) was dissolved in 10 mL of dry methylene chloride and pyridine (12 μL) by stirring under N 2 . The solution was cooled to 0°-5° C. and 12μL of trifluoromethane sulfonic anhydride was added (Step 9). After 1 hr, the solvent was removed in vacuo and the crude oil was chromatographed on silica gel using ethyl acetate/hexane (3 to 7). The product 11 (24 mg, 64%) showed a single spot on TLC (Rf=0.60) with the same solvent system; visualization was with MoO.H 3  PO 4 . 
     Synthesis of 3-  18  F!-fluoro-cyclobutane-1-amino-1-carboxylic acid   18  F!FACBC 13 
       18  F!-Fluoride was produced using the  18  O (p,n) 18  F reaction with 11 MeV protons on 95% enriched   18  O!water. After evaporation of the water and drying of the fluoride by acetonitrile evaporation, the protected amino acid triflate 11 (3 mg) was introduced in an acetonitrile solution (1 mL). The no carrier added (NCA) fluorination reaction (Step 10) was performed at 85° C. for 5 min in a sealed vessel in the presence of potassium carbonate and Kryptofix (Trademark Aldrich Chemical Co., Milwaukee, Wis. Unreacted  18  F- was removed by diluting the reacting mixture with methylene chloride followed by passage through a silica gel Seppak which gave the  18  F labeled product 12 in 42% E.O.B. yield. Deprotection of 12 (Step 11) was achieved by using 1 mL of 4N HCl at 115° C. for 15 min and then the aqueous solution containing  18  FACBC 13 was passed through an ion-retardation resin (AG 11A8 50-100 mesh). The synthesis was completed in 60 min following E.O.B. with an overall radiochemical yield of 12% (17.5% E.O.B.). 
     EXAMPLE 2 
     Synthesis of   18  F!-2-Amino-3-fluoro-2-methylpropane-1-carboxylic acid 24 (FAMPC) 3-Benzyloxy-1,2-epoxypropane 15 
     Sodium hydride (60% oil dispersion, 23.6 g, 0.59 mol) was added in portions to a solution of glycidol (14) (40 g, 0.54 mol), benzyl bromide (101.5 g, 0.59 mol), and n-butylammonium iodide (0.24 g) in dry DMF (150 mL) at 25° C. (Step 12). The mixture was stirred for 1 hr at 65° C., poured over ice and then extracted with ether (2×75 mL). The combined ether extract was washed with water (3×75 mL) and dried over MgSO 4 . Distillation using a 12-in vigreux column afforded 62.9 g (71%) of glycidyl benzyl ether 15; bp 120°-122° C. (10 mm);  1  H NMR (CDCl 3 ) δ2.6 (dd, 1H, OCHa), 2.8 (dd, 1H, OCHb), 3.2 (m, 1H, OCHc), 3.2 (dd, 1H, OCHd), 3.8 (dd, 1H, OCHe), 4.6 (dd, 2H, OCH 2 ), 7.23 (s, 5H, phenyl). 
     3-Benzyloxypropan-2-ol 16 
     To a suspension of lithium aluminum hydride (6.1 g, 0.16 mol) in ether (50 mL) at 25° C. was added a solution of glycidyl benzyl ether 15 (52.9 g, 0.32 mol) in 50 mL of ether (Step 13). The mixture was refluxed for 2 h and cooled to room temperature. A solution of 1N NaOH was added dropwise to the mixture and the precipitated metal salts were removed by filtration. The ether containing the product was washed with water (50 mL), dried (MgSO 4 ) and the solvent removed by roto-evaporation. Distillation gave 43.3 g (82%) of 3-benzyoxypropan-2-ol; 16 bp 110-112 (5 mm).  1  H NMR (CDCl 3 ) δ1.13 (d, J=6.6 Hz, 3H, CH 3 ), 2.5 (br s, 1H, OH), 3.28 (dd, 1H, OCH), 3.45 (dd, 1H, OCH), 4.0 (m, 1H, OCH), 4.55 (s, 2H, OCH 2 ), 7.35 (s, 5H, phenyl). ##STR6## 3-Benzyloxypropan-2-one 17 
     3-Benzyoxypropan-2-ol 16 (40 g, 0.24 mol) was added to a suspension of pyridinium chlorochromate (155.2 g, 0.72 mol) in DMF (150 ml) at 25° C., stirred at 65° C. for 3 h, and then diluted with water (75 mL) (Step 14). The mixture was extracted with ether (2×50 mL) and the combined ether layers were washed with water (3×50 mL) dried (MgSO 4 ) and the solvent removed by roto-evaporation. Distillation gave 31 g (77%) of 3-benzyloxypropan-2-one; 17 bp 104-106 (10 mm).  1  H NMR (CDCl 3 ) δ2.16 (s, 3H, CH 3 ), 4.05 (s, 1H, OH), 4.59 (s, 2H, OCH 2 ), 7.5 (s, 5H, phenyl). 
     2-(3-benzyloxypropane)hydantoin 18 
     3-Benzyloxypropan-2-one 17 (25 g, 0.15 mol) was dissolved in 300 mL of 50% ethanol containing ammonium carbonate (68.3 g, 0.60 mol) and potassium cyanide (19.5 g, 0.30 mol) was added. The mixture was warmed to 60° C. for 2 h and evaporated to dryness in vacuo (Step 15). The residue was extracted with 75 mL of hot methanol, filtered, and filter cake washed with 50 mL of hot methanol. The methanol solutions were combined, solvent evaporated, and the residue chromatographed on silica gel using CH 2  Cl 2  /methanol 90:10. Yield of 3-benzyloxypropan-2-one hydantoin 18 was 23 g (66%).  1  H NMR (d4-methanol) δ1.22 (s, 3H, CH 3 ), 3.41 (d, J=9.6 Hz, 1H, OCHa), 3.52 (d, J=9.6 Hz 1H, OCHb), 4.5 (s, 2H, NH), 4.8 (s, 2H, OCH 2 ), 8.25 (m, 5H, phenyl). 
     2-Amino-3-benzyloxy-2-methyl-1-propionic acid 19 
     The hydantoin 18 (6.0 g, 25.6 mmol) was hydrolyzed by refluxing with 20 mL of a barium hydroxide solution (saturated at room temperature) for 16 hr (Step 16). The solution was neutralized to pH 6 with 2M sulfuric acid and evaporated to dryness in vacuo. The residue was extracted with 50 mL of hot methanol, filtered, and washed with 50 mL of hot methanol. The methanol solutions were combined and evaporated. Yield of the amino acid 19 was 4.1 g (76%). 
     2-t-Butyl carbamate-3-benzyloxy-2-methyl-1-propionic acid 20 
     A solution of the amino acid 19 in 10 mL of a mixture of methanol-triethylamine (90:10) is treated with 1.0 g (4.6 mmol) of di-tert-butyl dicarbonate (Step 17). The mixture is heated at 50°-60° C. for 10 min and then the solvent removed by roto-evaporation. The crude product is stirred in 5 mL of dilute HCl (pH=2) at 0° C. for 10 min. The mixture is extracted with CH 2  Cl 2  (2×10 mL), the combined extract dried, and the solvent removed. The crude oil, 20, is chromatographed on Silica gel using methylene chloride/methanol (9 to 1) with 0.1% formic acid. 
     2-(t-Butyl carbamate)-3-benzyloxy-2-methyl-1-methylpropionate 21 
     To a slurry of 1-methyl-3-nitro-1-nitrosoguandine in ether at 0°-5° C. is added a 40% solution of potassium hydroxide dropwise. The resultant diazomethane ether solution is added to 1-t-butyl carbamate-3-benzyloxy-1-methylpropane-1-carboxylic acid 20 in 3 mL of ether and the mixture is stirred at room temperature for 15 min (Step 18). The mixture is washed with water (20 mL) and the ether evaporated. The crude residue 21 is chromatographed on silica gel using ethyl acetate/hexane (1 to 9). 
     2-(t-Butyl carbamate)-3-hydroxy-2-methyl-1-propionate 22 
     A solution of the protected amino acid benzyl ether 21 in 5 mL of methanol is mixed with a suspension of 25 mg of 10% palladium on charcoal in 5 mL of methanol (Step 19). The mixture is stirred under a positive pressure of hydrogen (balloon) for 16 hr. The catalyst is filtered off and the solvent is evaporated. The crude residue is chromatographed on silica gel using methylene chloride (9 to 1) to yield 22. 
     2-(t-Butyl carbamate)-3-trifluoromethane sulfonoxy-2-methyl-1-methylpropionate 23 
     The alcohol 22 is dissolved in 10 mL of dry methylene chloride and pyridine (12 μL) by stirring under N 2 . The solution is cooled to 0°-5° C. and 12 μL of trifluoromethane sulfonic anhydride is added (Step 20). After 1 hr, the solvent is removed in vacuo and the crude oil is chromatographed on silica gel using ethyl acetate/hexane (3:7) to yield 23. 
       18  F!-2-Amino-3-fluoro-2-methyl-1-propionic acid 24 
       18  F!-Fluoride is produced using the  18  O(p,n) 18  F reaction with 11 MeV protons on 95% enriched   18  O! water. After evaporation of the water and drying of the fluoride by acetonitrile evaporation, the protected amino acid triflate 23 (3 mg) is introduced in a acetonitrile solution (1 mL). The (NCA) fluorination reaction (Step 21) is performed at 85° C. for 5 min in a sealed vessel in the presence of potassium carbonate and Kryptofix. Unreacted  18  F -   is removed by diluting the reacting mixture with methylene chloride followed by passage through a silica gel Seppak which gives the  18  F labeled product. Deprotection (Step 22) is achieved by using 1 mL of 4N HCl at 115° C. for 15 min and then the aqueous solution is passed through an ion-retardation resin (AG 11A8 50-100 mesh) to yield 24. 
     EXAMPLE 3 
     Synthesis of   18  F!-1-Amino-3-fluorocyclopentane-1-carboxylic acid 37 (FACPC) 
     4-Bromo-1,2-epoxybutane 26 
     A solution of m-chloroperbenzoic acid (50% pure, 72.5 g, 0.21 mol) in 500 mL of methylene chloride was added dropwise to a stirred ice-cooled solution of 4-bromo-1-butene 25 (25 g, 0.19 mol) in 100 mL of methylene chloride (Step 23). After the addition, the mixture was stirred at 25° C. for 18 h, during which time m-chlorobenzoic acid precipitated. The reaction mixture was washed with 4N sodium hydroxide until the aqueous phase remained alkaline and with water until neutral. The organic phase was dried (MgSO 4 ) and the solvent removed in vacuo to give 27.9 g (89%) of 4-bromo-1,2-epoxybutane 26.  1  H NMR (CDCl 3 ) δ2.10 (m, 2H, O--C--CH 2 ), 2.58 (d,d J=5.0, 2.6 Hz, 1H, OCHa) 2.82 (dd J=5.0,4.0 Hz), 1H, OCH b ), 3.09 (m, 2H, O-C-CH 2 , 3.55 (t, J=7 Hz, 2H). 
     Diethyl 3-hydroxycyclopentane-1,1-dicarbonate 27 
     A solution of diethyl malonate (7.7 g, 48.5 mmol) in 53.4 mL of 1N ethanolic sodium ethoxide was stirred for 15 min in a ice bath, after which 4-bromo-1,2-epoxybutane 26 (14.6 g, 97 mmol) was added (Step 24). After stirring at 25° C. for 3 h, the mixture was poured into water and the ethanol evaporated in vacuo. The aqueous solution was extracted with chloroform, the extracts dried (MgSO 4 ) and concentrated. Distillation gave 8.14 g (73%) of product 27; bp 155°-160° C. (0.5 mm);  1  H NMR (CDCl 3 ) δ1.3 (t, J=7.2 Hz, 6H, CH 3 ), 1.7-2.7 (m, 6H, CH 2 ), 3.02 (s, 1H, OH), 4.2 (q, J=7.2 Hz, 4H, O═COCH 2 ), 4.2 (m, 1H, OCH). 
     Diethyl 3-benzyloxycyclopentane-1,1-dicarboxylate 28 
     Sodium hydride (60% oil dispersion, 2.1 g, 53 mmol) was added in portions to a solution of diethyl 3-hydroxycyclopentane-1,1-dicarboxylate 27 (11 g, 48 mmol), benzyl bromide (9.7 g, 53 mol), and n-tetrabutylammonium iodide (100 mg) in dry DMF (50 mL) at 25° C. (Step 25). The mixture was stirred for 1 hr at 65° C., poured onto ice and then extracted with ether (2×50 mL). The combined either extract was washed with water (3×50 mL) and driedover MgSO 4 . Chromatography on silica gel (10:90 ethyl acetate/hexane, Rf=0.38) afforded 11.6 g (75%) of the benzyl ether 28;  1  H NMR (CDCl 3 ) δ1.3 (t, J=7.2 Hz, 6H, CH 3 ), 1.7-2.7 (m, 6H, CH 2 ), 4.2 (q, J=7.2 Hz, 4H, O═COCH 2 ), 4.1 (m, 1H, O--CH), 4.6 (s, 2H, O--CH 2 ), 7.3 (s, 5H, phenyl). 
     3-Benzyloxycyclopentane-1,1-dicarboxamine 29 
     Diethyl 3-benzyloxycyclopentane-1,1-dicarboxylate 28 (10 g, 31 mmol) is stirred with concentrated aqueous ammonia (100 mL) for four days at room temperature (Step 26). The resultant diamide 29 is collected by filtration and washed with water followed by ethyl acetate. 
     Cis/trans 5-(3-benzyloxycyclopentane)hydantoin 30 
     3-Benzyloxycyclopentane-1,1-dicarboxamine 29 is stirred in 150 mL of dilute sodium hypochlorite (Aldrich product/water ##STR7## 1:2) at 0°-5° C. for 4 hr and then allowed to stand overnight at room temperature (Step 26). Unreacted diamide will be recovered by filtration. The solution is neutralized to pH 5 with concentrated hydrochloric acid and evaporated to dryness in vacuo. The residue is extracted with 50 mL of hot methanol, filtered, and washed with 50 mL of hot methanol. The methanol solutions are combined and evaporated. 
     1-Amino-3-benzyloxycylcopentanecarboxylate acid 31 
     The hydantoin 30 is hydrolyzed by refluxing with 10 mL of a barium hydroxide solution (saturated at room temperature) for 16 hr (Step 28). The solution is neutralized to pH 6 with 2M sulfuric acid and evaporated to dryness in vacuo. The residue is extracted with 50 mL of hot methanol, filtered, and washed with 50 mL of hot methanol. The methanol solutions are combined and evaporated. 
     1-t-Butyl carbamate-3-benzyloxy-1-cyclopentane-1-carboxylic acid 32 
     A solution of the amino acid 31 in 10 mL of a mixture of methanol/triethylamine (90:10) is treated with di-tert-butyl dicarbonate (Step 29). The mixture is heated at 50°-60° C. for 10 min and then the solvent is removed by rotoevaporation. The crude product is stirred in 5 mL of dilute HCl (pH=2) at 0° C. for 10 min. The mixture is extracted with CH 2  Cl 2  (2×10 mL), the combined extract dried, and the solvent removed. The crude oil is chromatographed on silica gel using methylene chloride/methanol (9 to 1) with 0.1% formic acid to yield 32. 
     1-t-Butyl carbamate-3-benzyloxy-1-cyclopentane-1-carboxylic acid methyl ester 33 
     To a slurry of 1-methyl-3-nitro-1-nitrosoguandine in ether at 0°-5° C. will be added to a 40% solution of potassium hydroxide dropwise. The resultant diazomethane ether solution is added to 1-t-butyl carbamate-3-benzyloxycyclopentane-1-carboxylic acid 32 in 3 mL of ether and the mixture is stirred at room temperature for 15 min (Step 30). The mixture is washed with water (10 mL) and the ether evaporated. The crude residue is chromatographed on silica gel using ethyl acetate/hexane (1 to 9) to yield 33. 
     1-t-Butyl carbamate-3-hydroxy-1-cyclopentane-1-carboxylic acid methyl ester 34 
     A solution of the protected amino acid benzyl ether 33 in 5 mL of methanol is mixed with a suspension of 25 mg of 10% palladium on charcoal in 5 mL of methanol (Step 31). The mixture is stirred under a positive pressure of hydrogen (balloon) for 16 hr. The catalyst is filtered off and the solvent is evaporated. The crude residue is chromatographed on silica gel using methylene chloride/methanol (9 to 1) to yield 34. 
     1-t-Butyl carbamate-3-trifluoromethane sulfonoxy-1-cyclopentane-1-carboxylic acid methyl ester 35 
     The alcohol is dissolved in 10 mL of dry methylene chloride and pyridine (12 μL) by stirring under N 2 . The solution is cooled to 0°-5° C. and 12 μL of trifluoromethane sulfonic anhydride is added (Step 32). After 1 hr, the solvent is removed in vacuo and the crude oil is chromatographed on silica gel using ethyl acetate/hexane (3:7) to yield 35. 
       18  F!-1-Amino-3-fluorocyclopentane-1-carboxylic acid 37 
       18  F!-Fluoride will be produced using the  18  O(p,n) 18  F reaction with 11 MeV protons on 95% enriched   18  O! water. After evaporation of the water and drying of the fluoride by acetonitrile evaporation, the protected amino acid triflate 35 (3 mg) is introduced in an acetonitrile solution (1 mL). The (NCA) fluorination reaction is performed at 85° C. for 5 min in a sealed vessel in the presence of potassium carbonate and Kryptofix (Step 33). Unreacted  18  F -   is removed by diluting the reacting mixture with methylene chloride followed by passage through a silica gel Seppak which gives the  18  F labeled product 36. Deprotection (Step 34) is achieved by using 1 mL of 4N HCl at 115° C. for 15 min and then the aqueous solution is passed through an ion-retardation resin (AG 11A8 50-100 mesh) to yield 37 (FACPC). 
     EXAMPLE 4 
       18  F!-1-Amino-4-fluoro-cyclohexane-1-carboxylic acid 49 (FACHC) 
     4-Hydroxycyclohexanone ethylene ketal 49 
     Sodium borohydrate (2.4 g, 64 mmol) was added in portions to a stirred ice cold solution of 1,4 cyclohexanedione monoethylene ketal 38 (20 g, 128 mmol) in 60 mL of methanol (Step 35). After addition was complete, 1N HCl was added to the solution dropwise until a pH of 8 was obtained and then the solvent was removed by roto-evaporation. The product 39 (16.8 g, 84%) showed a single spot on TLC (Rf=0.4, ethyl acetate/hexane 20:80 solvent system, visualization was with acidic vanillin ethanol solution) and was used without further purification.  1  H NMR (CDCl 3 ) δ1.6-1.9 (m, 8H, ring-CH 2 ), 3.8 (m, 1H, CH--O), 4.0 (s, 4H, ketal-CH 2 ), 5.3 (s, 1H, OH). 
     4-Benzyloxycyclohexanone ethylene ketal 40 
     Sodium hydride (60% oil dispersion, 2.2 g, 56 mmol) was added in portions to a solution of 6-hydroxycyclohexanone ethylene ketal (39) (8.8 g, 51 mmol), benzyl bromide (9.6 g, 5.6 mmol), and tetra-n-butylammonium iodide (50 mg) in dry DMF (50 mL) at 25° C. (Step 36). The mixture was stirred for 1 hr at 65° C., poured over ice and then extracted with ether (2×50 mL). The combined ether extract was washed with water (3×50 mL), dried (MgSO 4 ) and solvent was removed. Chromatography on silica gel using 10:90 ethyl acetate/hexane (Rf=0.39) afforded 8.9 g (70%) of the benzyl ether 40.  1  H NMR (CDCl 3 ) δ1.6-1.9 (m, 8H, ring-CH 2 ), 3.6 (m, 1H, CH--O), 4.0 (2, 4H, ketal-CH 2 ), 4.6 (s, 2H, CH 2  --O). 
     4-Benzyloxycyclohexanone 41 
     A solution of 4-benzyloxy cyclohexanone ethylene ketal 40 (5.0 g, 20.1 mmol) in methanol (20 mL) and 1N HCl (0.5 mL) was stirred overnight at 25° C. (Step 37). The mixture was neutralized by addition of 1N NaHCO 3  (0.5 mL), solvent removed by roto-evaporation, and the residue chromatographed on silica gel using 15:85 ethyl acetate /hexane. Yield of the ketone 41 was 2.7 g ##STR8## (67%); Rf=0.35;  1  H NMR (CDCl 3 ) δ2.3 (m, 8H, ring-CH 2 ), 3.6 (m, 1H, CH--O ), 4.6 (s, 2H, CH 2  --O). 
     4-Benzyloxycyclohexanone hydantoin 42 
     4-Benzyloxycyclohexanone 41 is dissolved in 30 mL of 50% ethanol containing ammonium carbonate and potassium cyanide is added (Step 38). The mixture will be warmed to 60° C. for 2 h and evaporated to dryness in vacuo. The residue is extracted with 40 mL of hot methanol, filtered, and the filter cake washed with 20 mL of hot methanol. The methanol solutions are combined, solvent evaporated, and the residue chromatographed on silica gel using CH 2  Cl 2  /methanol 90:10 to yield 42. 
     1-Amino-4-benzyloxycyclohexane-1-carboxylic acid 43 
     The hydantoin 42 is hydrolyzed by refluxing with 10 mL of a barium hydroxide solution (saturated at room temperature) for 16 h (Step 39). The solution is neutralized to pH 6 with 2N sulfuric acid and evaporated to dryness in vacuo. The residue is extracted with 50 mL of hot methanol, filtered, and washed with 50 mL of hot methanol. The methanol solutions are combined and evaporated. 
     1-t-Butyl carbamate-3-benzyloxy-1-cyclohexane-1-carboxylic acid 44 
     A solution of the amino acid in 10 mL of a mixture of methanol/triethylamine (90:10) is treated with di-tert-butyl dicarbonate (Step 40). The mixture is heated at 50°-60° C. for 10 min and then the solvent is removed by rotoevaporation. The crude product is stirred in 5 mL of dilute HCl (pH=2) at 0° C. for 10 min. The mixture is extracted with CH 2  Cl 2  (2×10 mL), the combined extract dried, and the solvent removed. The crude oil is chromatographed on silica gel using methylene chloride/methanol (9 to 1) with 0.1% formic acid to yield 44. 
     1-t-Butyl carbamate-3-benzyloxy-1-cyclohexane-1-carboxylic acid methyl ester 45 
     To a slurry of 1-methyl-3-nitro-1-nitrosoguandine in ether at 0°-5° C. is added to a 40% solution of potassium hydroxide dropwise. The resultant diazomethane ether solution is added to 1-t-Butyl carbamate-3-benzyloxy-1-cyclohexane-1-carboxylic acid 44 in 3 mL of ether and the mixture is stirred at room temperature for 15 min (Step 41). The mixture is washed with water (10 mL) and the ether evaporated. The crude residue is chromatographed on silica gel using ethyl acetate/hexane (1 to 9) to yield 45. 
     1-t-Butyl carbamate-3-hydroxy-1-cyclobutane-1-carboxylic acid methyl ester 46 
     A solution of the protected amino acid benzyl ether 45 in 5 mL of methanol is mixed with a suspension of 25 mg of 10% palladium on charcoal in 5 mL of methanol (Step 42). The mixture is stirred under a positive pressure of hydrogen (balloon) for 16 hr. The catalyst is filtered off and the solvent is evaporated. The crude residue is chromatographed on silica gel using methylene chloride/methanol (9 to 1) to yield 46. 
     1-t-Butyl carbamate-3-trifluoromethane sulfonoxy-1-cyclohexane-1-carboxylic acid methyl ester 47 
     The alcohol 46 is dissolved in 10 mL of dry methylene chloride and pyridine (12 μL) by stirring under N 2 . The solution is cooled to 0°-5° C. and 12 μL of trifluoromethane sulfonic anhydride is added (Step 43). After 1 hr, the solvent is removed in vacuo and the crude oil is chromatographed on silica gel using ethyl acetate/hexane (3:7). 
       18  F!-1-Amino-3-fluorocyclohexane-1-carboxylic acid 49 
       18  F!-Fluoride is produced using the  18  O(p,n) 18  F reaction with 11 MeV protons on 95% enriched   18  O! water. After evaporation of the water and drying of the fluoride by acetonitrile evaporation, the protected amino acid triflate 47 (3 mg) is introduced in an acetonitrile solution (1 mL). The (NCA) fluorination reaction is performed at 85° C. for 5 min in a sealed vessel in the presence of potassium carbonate and Kryptofix (Step 44). Unreacted  18  F -   is removed by diluting the reacting mixture with methylene chloride followed by passage through a silica gel Seppak which gives the  18  F labeled product. Deprotection (Step 45) is achieved by using 1 mL of 4N HCl at 115° C. for 15 min and then the aqueous solution is passed through an ion-retardation resin (AG 11A8 50-100 mesh) to yield FACHC 49. 
     EXAMPLE 5 
       18  F!-1-Amino-3-(fluoromethyl)cyclobutane-1-carboxylic acid 60 
     Dimethyl ester 3-hydroxycyclobutane-1,1-dicarboxylate 51 
     To a slurry of 1-methyl-3-nitro-1-nitrosoguandine (150 mg) in 8 mL of ether at 0°-5° C. was added a 40% solution of potassium hydroxide dropwise. The resultant diazomethane ether solution was added to 0.15 g (0.50 mmol) of 50 in 3 mL of ether and the mixture was stirred at room temperature for 15 min (Step 46). The mixture was washed with water (10 mL) and the ether evaporated. The crude residue was chromatographed on Silica gel. 
     Dimethyl 3-(benzyloxymethyl)cyclobutane-1,1-dicarboxylate 52 
     Sodium hydride (60% oil dispersion, 2.1 g, 53 mmol) is added in portions to a solution of dimethyl 3-(hydroxymethyl) cyclobutane-1,1-dicarboxylate (51), benzyl bromide, and n-tetrabutylammonium iodide in dry DMF at 25° C. (Step 47). The mixture is stirred for 1 hr at 65° C., poured onto ice and then extracted with ether (2×50 mL). The combined ether extract is washed with water (3×50 mL) and dried over MgSO 4 . Chromatography on silica gel. ##STR9## 3-(Benzyloxymethyl)cyclobutane-1,1-dicarboxamine 53 
     Dimethyl 3-(benzyloxymethyl)cyclobutane-1,1-dicarboxylate (52) is stirred with concentrated aqueous ammonia (100 mL) for four days at room temperature (Step 48). The resultant diamide is collected by filtration and washed with water followed by ethyl acetate. 
     Cis/trans 5-((3-benzyloxymethyl)cyclobutane)hydantoin 54 
     3-(Benzyloxymethyl)cyclopentane-1,1-dicarboxamine (53) is stirred with dilute sodium hypochlorite (Aldrich product/water 1:2) at 0°-5° C. for 4 hr and then allowed to stand overnight at room temperature (Step 49). Unreacted diamide is recovered by filtration. The solution is neutralized to pH 5 with concentrated hydrochloric acid and evaporated to dryness in vacuo. The residue is extracted with 50 mL of hot methanol, filtered, and washed with 50 mL of hot methanol. The methanol solutions are combined and evaporated. 
     1-Amino-3-(benzyloxymethyl)cyclobutane-1-carboxylic acid 55 
     The hydantoin 54 is hydrolyzed by refluxing with 10 mL of a barium hydroxide solution (saturated at room temperature) for 16 hr (Step 50). The solution is neutralized to pH 6 with 2M sulfuric acid and evaporated to dryness in vacuo. The residue is extracted with 50 mL of hot methanol, filtered, and washed with 50 mL of hot methanol. The methanol solutions are combined and evaporated. 
     1-t-Butyl carbamate-3-(benzyloxymethyl)cyclobutane-1-carboxylic acid 56 
     A solution of the amino acid (55) in 10 mL of a mixture of methanol/triethylamine (90:10) is treated with di-tert-butyl dicarbonate (Step 51). The mixture is heated at 50°-60° C. for 10 min and then the solvent is removed by rotoevaporation. The crude product is stirred in 5 mL of dilute HCl (pH=2) at 0° C. for 10 min. The mixture is extracted with CH 2  Cl 2  (2×10 mL), the combined extract dried, and the solvent removed. The crude oil is chromatographed on silica gel using methylene chloride/methanol (9 to 1) with 0.1% formic acid. 
     1-t-Butyl carbamate-3-(benzyloxymethyl)cyclobutane-1-carboxylic acid methyl ester 57 
     To a slurry of 1-methyl-3-nitro-1-nitrosoguandine in ether at 0°-5° C. is added a 40% solution of potassium hydroxide dropwise. The resultant diazomethane ether solution is added to carboxylic acid 56 in ether and the mixture is stirred at room temperature for 15 min. (Step 52). The mixture is washed with water and the ether evaporated. The crude residue is chromatographed on silica gel using ethyl acetate/hexane (1 to 9). 
     1-t-Butyl carbamate-3-(hydroxymethyl)cyclobutane-1-carboxylic acid methyl ester 58 
     A solution of the protected amino acid benzyl ether 57 in methanol is mixed with a suspension of 10% palladium on charcoal in 5 mL of methanol (Step 53). The mixture is stirred under a positive pressure of hydrogen (balloon) for 16 hr. The catalyst is filtered off and the solvent is evaporated. The crude residue is chromatographed on silica gel using methylene chloride/methanol (9 to 1). 
     1-t-Butyl carbamate-3-(trifluoromethane sulfonoxymethyl) cyclobutane-1-carboxylic acid methyl ester 59 
     The alcohol 58 is dissolved in 10 mL of dry methylene chloride and pyridine (12 μL) by stirring under N 2 . The solution is cooled to 0°-5° C. and 12 μL of trifluoromethane sulfonic anhydride is added (Step 54). After 1 hr, the solvent is removed in vacuo and the crude oil is chromatographed on silica gel using ethyl acetate/hexane (3:7). 
       18  F!-1-Amino-3-(fluoromethyl)cyclobutane-1-carboxylic acid 60 
       18  F!-Fluoride is produced using the  18  O(p,n) 18  F reaction with 11 MeV protons on 95% enriched   18  O! water. After evaporation of the water and drying of the fluoride by acetonitrile evaporation, the protected amino acid triflate 58 (3 mg) is introduced in an acetonitrile solution (1 mL). The (NCA) fluorination reaction is performed at 85° C. for 5 min in a sealed vessel in the presence of potassium carbonate and Kryptofix (Step 55). Unreacted  18  F -   is removed by diluting the reacting mixture with methylene chloride followed by passage through a silica gel Seppak which gives the  18  F labeled product. Deprotection of 59 is achieved by using 1 mL of 4N HCl at 115° C. for 15 min (Step 56) and then the aqueous solution is passed through an ion-retardation resin (AG 11A8 50-100 mesh). 
     EXAMPLE 6 
     Synthesis of   123  I!1-Amino-3-iodocyclobutane-1-carboxylic acid 61 
       123  I!-Sodium iodide (10 mCi, 0.1N NaOH solution) is dried by acetonitrile (2 mL) evaporation, the protected amino acid triflate 11 (3 mg) is introduced in an acetonitrile solution (1 mL) (Step 57). The (NCA) iodination reaction is performed at 85° C. for 5 min in a sealed vessel. Unreacted  18  F -   is removed by diluting the reacting mixture with methylene chloride followed by passage through a silica gel Seppak which gives the  18  I labeled product. Deprotection is achieved by using 1 mL of 4N HCl at 115° C. for 15 min (Step 58) and then the aqueous solution is passed through an ion-retardation resin (AG 11A8 50-100 mesh). 
     EXAMPLE 7 
     Synthesis of   123  I!-1-Amino-3-iodocyclobut-2-ene-1-carboxylic acid 65 
     1-t-Butyl carbamate-3-oxo-1-cyclobutane-1-carboxylic acid methyl ester 62 
     The protected alcohol 10 is added to a suspension of pyridinium chlorochromate in DMF at 25° C., stirred at 65° C. for 3 h, and then diluted with water (75 mL) (Step 59). The mixture is extracted with ether (2×50 mL) and the combined ether layers were washed with water, dried (MgSO4) and the solvent removed by roto-evaporation. 
      1-t-Butyl carbamate-1-cyclobutane-1-carboxylic acid methyl ester! 3-hydrazone 63 
     A mixture of hydrazine, ketone 62, DBN, and 20 mL of ethanol is heated to boiling (Step 60). The mixture is kept hot for 10 min. The solution is cooled, and the hydrazone is collected by filtration. 
       123  I!-1-Amino-3-iodo-cyclobut-2-ene-1-carboxylic acid 65 
     Aqueous 3% hydrogen peroxide is added to a mixture of sodium   123  I!iodide, hydrazone 63, and 0.1N HCl in a sealed vial protected by a charcoal vent (Step 61). The reaction is allowed to proceed for 30 min at ambient temperature, quenched with a solution of sodium bisulfite (300 mg/mL). Deprotection of 64 (Step 62) is achieved by using 1 mL of 4N HCl at 115° C. for 15 min and then the aqueous solution is passed through an ion-retardation resin (AG 11A8 50-100 mesh). 
     EXAMPLE 8 
     Synthesis of E-  123  I!-1-Amino-3-(2-iodoethenyl)cyclobutane-1-carboxylic acid 69 
     1-t-Butyl carbamate-3-bromo-1-cyclobutane-1-carboxylic acid methyl ester 66 
     Bromine is added to a mixture of alcohol 10 and triphenylphosphine in DMF at -10° C. (Step 63). After stirring for 1 h, the mixture is diluted with water and extracted with ether. The ether layer is washed with water, 10% sodium sulfite, and then dried. The ether is removed and the residue is chromatographed on silica gel. 
     1-t-Butyl carbamate-3-ethynyl-1-cyclobutane-1-carboxylic acid methyl ester 67 
     The bromo compound 66 in THF is added to a suspension of lithium acetylide ethylenediamine complex in THF stirred at 0° C. under a nitrogen atmosphere (Step 64). The mixture is stirred for 3 h at 25° C., poured into ice water, and extracted with ether. The ether extract is washed with ice cold 1N HCl, brine and then dried. The ether is removed and the residue is chromatographed on silica gel. ##STR10## 1-t-Butyl carbamate-3-((E)-2-tributylstannylethenyl)-1-cyclobutane-1-carboxylic acid methyl ester 68 
     Tributyltin hydride, the alkyne 67 and azobisisobutyronitrile are refluxed in toluene under nitrogen atmosphere for 10 h (Step 65). The reaction mixture is cooled, solvent removed in vacuo, and the residue chromatographed on silica gel. 
       123  I!-1-Amino-3-((E)-2-iodoethenyl)cyclobut-2-ene-1-carboxylic acid 69 
     Aqueous 3% hydrogen peroxide is added to a mixture of sodium   125  I!iodide, tributylstannyl 68, and 0.1N HCl in a sealed vial protected by a charcoal vent (Step 66). The reaction is allowed to proceed for 30 min at ambient temperature, quenched with a solution of sodium bisulfite (300 mg/mL). Deprotection (Step 67) is achieved by using 1 mL of 4N HCl at 115° C. for 15 min and then the aqueous solution is passed through an ion-retardation resin (AG 11A8 50-100 mesh). 
     EXAMPLE 9 
     Synthesis of   123  I!-1-Amino-3-(iodomethylenyl)cyclobutane-1-carboxylic acid 
     (Bromomethyl)triphenylphosphonium bromide 70 
     A mixture of hydroxymethyl)triphenylphosphonium bromide and phosphorus tribromide in benzene is heated at reflux for 23 h with stirring. After this time the solution is dark orange and an orange solid is present. The mixture is cooled to 25° C. and methanol is added. The solvent was removed at reduced pressure and the residue treated with water to extract the phosphonium salt. The aqueous extracts were saturated with solid potassium bromide and extracted with chloroform. The phosphonium salts are crystallized from hot chloroform by addition of ethyl acetate. 
     1-t-Butyl carbamate-3-(bromomethylenyl)-1-cyclobutane-1-carboxylic acid methyl ester 71 
     The phosphonium salt 70 is suspended in ether and ethereal phenyllithium is added rapidly at 25° C. An orange-yellow solution results which becomes mustard yellow within 2 h. To this solution is added protected ketone 62 and the reaction mixture is heated at ##STR11## reflux for 8 h with stirring (Step 68). The ether is removed and the residue is chromatographed on silica gel. 
     1-t-Butyl carbamate-3-(tributylstannylmethylenyl)-1-cyclobutane-1-carboxylic acid methyl ester 72 
     To a solution of 71 in ether at -78° C. is added t-butyllithium (2 eq.) after 15 min tributyltin chloride is added and the mixture is warmed to 25° C. (Step 69). The reaction mixture is poured into ice water and the ether layer separated and dried. The ether is removed and the residue is chromatographed on silica gel. 
       123  I!-1-Amino-3-(iodomethylenyl)cyclobutane-1-carboxylic acid 74 
     Aqueous 3% hydrogen peroxide is added to a mixture of sodium   125  I!iodide, tributylstannyl 72, and 0.1N HCl in a sealed vial protected by a charcoal vent (Step 70). The reaction is allowed to proceed for 30 min at ambient temperature, quenched with a solution of sodium bisulfite (300 mg/mL). Deprotection of 73 (Step 71) is achieved by using 1 mL of 4N HCl at 115° C. for 15 min and then the aqueous solution is passed through an ion-retardation resin (AG 11A8 50-100 mesh). 
     EXAMPLE 10 
       123  I!-2-Amino-2-methyl-4-(E)-iodobut-3-en-1-oic acid 
     2-t-Butyl carbamate-2-methyl-3-carbomethoxy propanol 75 
     The protected alcohol 22 is added to a suspension of pyridinium chlorochromate in DMF at 25° C., stirred at 65° C. for 3 h, and then diluted with water (75 mL) (Step 72). The mixture is extracted with ether (2×50 mL) and the combined ether layers were washed with water, dried (MgSo 4 ) and the solvent removed by roto-evaporation. 
     2-t-Butyl carbamate-2-methyl-4-(E)-bromobut-3-en-1-oic acid methyl ester 76 
     The phosphonium salt 70 is suspended in ether and ethereal phenyllithium is added rapidly at 25° C. An orange-yellow solution results which becomes mustard yellow within 2 h. To this solution is added protected aldehyde 75 and the reaction mixture is heated ##STR12## at reflux for 8 h with stirring (Step 73). The ether is removed and the residue is chromatographed on silica gel. 
     2-t-Butyl carbamate-2-methyl-4-(E)-tributylstannylbut-3-en-1-oic acid methyl ester 77 
     To a solution of 76 in ether at -78° C. will be added t-butyllithium (2 eq.) after 15 min tributyltin chloride is added and the mixture is warmed to 25° C. (Step 74). The reaction mixture is poured into ice water and the ether layer separated and dried. The ether is removed and the residue is chromatographed on silica gel. 
       123  I!-2-Amino-2-methyl-4-(E)-iodobut-3-en-1-oic acid 79 
     Aqueous 3% hydrogen peroxide is added to a mixture of sodium   123  I!iodide, tributylstannyl 77, and 0.1N HCl in a sealed vial protected by a charcoal vent (Step 75). The reaction is allowed to proceed for 30 min at ambient temperature, quenched with a solution of sodium bisulfite (300 mg/mL). Deprotection of 78 (Step 76) is achieved by using 1 mL of 4N HCl at 115° C. for 15 min and then the aqueous solution is passed through an ion-retardation resin (AG 11A8 50-100 mesh). 
     EXAMPLE 11 
     Synthesis of   123  I!-1-Amino-3-iodocyclopentane-1-carboxylic acid 80 
       125  I!-Sodium iodide (10 mCi, 0.1N NaOH solution) is dried by acetonitrile (2 mL) evaporation, the protected amino acid triflate 35 (3 mg) is introduced in an acetonitrile solution (1 mL). The (NCA) iodination reaction is performed at 85° C. for 5 min in a sealed vessel. Unreacted  123  I is removed by diluting the reacting mixture with methylene chloride followed by passage through a silica gel Seppak which gives the  123  I labeled product. Deprotection is achieved by using 1 mL of 4N HCl at 115° C. for 15 min and then the aqueous solution is passed through an ion-retardation resin (AG 11A8 50-100 mesh). ##STR13## 
     EXAMPLE 12 
     Synthesis of   123  I!-1-Amino-3-iodocyclopent-2-ene-1-carboxylic acid 
     1-t-Butyl carbamate-3-oxo-1-cyclopentane-1-carboxylic acid methyl ester 81 
     The protected alcohol 34 will be added to a suspension of pyridinium chlorochromate in DMF at 25° C., stirred at 65° C. for 3 h, and then diluted with water (75 mL) (Step 77). The mixture is extracted with ether (2×50 mL) and the combined ether layers are washed with water, dried (MgSO 4 ) and the solvent removed by roto-evaporation. 
      1-t-Butyl carbamate-1-cyclopentane-1-carboxylic acid methyl ester! 3-hydrazone 82 
     A mixture of hydrazine, the ketone 81, DBN, and 20 mL of ethanol is heated to boiling (Step 78). The mixture is kept hot for 10 min. The solution is cooled, and the hydrazone is collected by filtration. 
       123  I!-1-Amino-3-iodo-cyclopent-2-ene-1-carboxylic acid 84 
     Aqueous 3% hydrogen peroxide will be added to a mixture of sodium   123  I!iodide, hydrazone 82, and 0.1N HCl in a sealed vial protected by a charcoal vent (Step 79). The reaction is allowed to proceed for 30 min at ambient temperature, quenched with a solution of sodium bisulfite (300 mg/mL). Deprotection of 83 (Step 80) is achieved by using 1 mL of 4N HCl at 115° C. for 15 min and then the aqueous solution is passed through an ion-retardation resin (AG 11A8 50-100 mesh). 
     EXAMPLE 13 
     Synthesis of E-  123  I!-1-Amino-3-(2-iodoethenyl cyclopentane-1-carboxylic acid 88 
     1-t-Butyl carbamate-3-bromo-1-cyclopentane-1-carboxylic acid methyl ester 85 
     Bromine is added to a mixture of alcohol 34 and triphenylphosphine in DMF at -10° C. (Step 81). After stirring for 1 h, the mixture is diluted with water and extracted with ether. The ether layer is washed with water, 10% sodium sulfite, and then dried. The ether is removed and the residue is chromatographed on silica gel. 
     1-t-Butyl carbamate-3-ethynyl-1-cyclopentane-1-carboxylic acid methyl ester 86 
     The bromo compound 85 in THF is added to a suspension of lithium acetylide ethylenediamine complex in THF stirred at 0° C. under a nitrogen atmosphere (Step 82). The mixture is stirred for 3 h at 25° C., poured into ice water, and extracted with ether. The ether extract is washed with ice cold 1N HCl, brine and then dried. The ether is removed and the residue is chromatographed on silica gel. 
     1-t-Butyl carbamate-3-((E)-2-tributylstannylethenyl)-1-cyclopentane-1-carboxylic acid methyl ester 87 
     Tributyltin hydride, the alkyne 86 and azobisisobutyronitrile will be refluxed in toluene under nitrogen atmosphere for 10 h (Step 83). The reaction mixture is cooled, solvent removed in vacuo, and the residue chromatographed on silica gel. 
       123  I!-1-Amino-3-((E)-2-iodoethenyl)cyclopentane-1-carboxylic acid 88 
     Aqueous 3% hydrogen peroxide is added to a mixture of sodium   123  I!iodide, tributylstannyl 87, and 0.1N HCl in a sealed vial protected by a charcoal vent (Step 84). The reaction is allowed to proceed for 30 min at ambient temperature, quenched with a solution of sodium bisulfite (300 mg/mL). Deprotection (Step 85) is achieved by using 1 mL of 4N HCl at 115° C. for 15 min and then the aqueous solution is passed through an ion-retardation resin (AG 11A8 50-100 mesh). ##STR14## 
     EXAMPLE 14 
     Synthesis of   123  I!-1-Amino-3-(iodomethylenyl)cyclopentane-1-carboxylic acid 93 1-t-Butyl carbamate-3-(bromomethylenyl)-1-cyclopentane-1-carboxylic acid methyl ester 90 
     The phosphonium salt 70 is suspended in ether and ethereal phenyllithium is added rapidly at 25° C. An orange-yellow solution results which becomes mustard yellow within 2 h. To this solution is added protected ketone 81 and the reaction mixture is heated at reflux for 8 h with stirring (Step 86). The ether is removed and the residue is chromatographed on silica gel. 
     1-t-Butyl carbamate-3-(tributylstannylmethylenyl)-1-cyclopentane-1-carboxylic acid methyl ester 91 
     To a solution of 90 in ether at -78° C. is added t-butyllithium (2 eq.) after 15 min tributyltin chloride is added and the mixture is warmed to 25° C. (Step 87). The reaction mixture is poured into ice water and the ether layer separated and dried. The ether is removed and the residue is chromatographed on silica gel. 
       123  I!-1-Amino-3-(iodomethylenyl)cyclopentane-1-carboxylic acid 93 
     Aqueous 3% hydrogen peroxide is added to a mixture of sodium   123  I!iodide, tributylstannyl 91, and 0.1N HCl in a sealed vial protected by a charcoal vent (Step 88). The reaction is allowed to proceed for 30 min at ambient temperature, quenched with a solution of sodium bisulfite (300 mg/mL). Deprotection of 92 (Step 89) is achieved by using 1 mL of 4N HCl at 115° C. for 15 min and then the aqueous solution is passed through an ion-retardation resin (AG 11A8 50-100 mesh). 
     EXAMPLE 15 
     Synthesis of   123  I!-1-Amino-4-iodocyclohexane-1-carboxylic acid 94 
       123  I!-Sodium iodide (10 mCi, 0.1N NaOH solution) will be dried by acetonitrile (2 mL) evaporation, the protected amino acid triflate 46 (3 mg) is introduced in an acetonitrile solution (1 mL). The (NCA) iodination reaction is performed at 85° C. for 5 min in a sealed vessel. Unreacted  123  I is removed by diluting the reacting mixture with methylene chloride followed by passage through a silica gel Seppak which gives the  123  I labeled product. Deprotection is achieved by using 1 mL of 4N HCl at 115° C. for 15 min and then the aqueous solution is passed through an ion-retardation resin (AG 11A8 50-100 mesh). 
     EXAMPLE 16 
     Synthesis of   123  I!1-Amino-4-iodocyclohex-2-ene-1-carboxylic acid 
     1-t-Butyl carbamate-4-oxo-1-cyclohexane-1-carboxylic acid methyl ester 95 
     The protected alcohol 46 is added to a suspension of pyridinium chlorochromate in DMF at 25° C., stirred at 65° C. for 3 h, and then diluted with water (75 mL) (Step 77). The mixture is extracted with ether (2×50 mL) and the combined ether layers are washed with water, dried (MgSO4) and the solvent removed by roto-evaporation. 
      1-t-Butyl carbamate-1-cyclohexane-1-carboxylic acid methyl ester! 4-hydrazone 96. 
     A mixture of hydrazine, the ketone 95, and 20 mL of ethanol is heated to boiling, and a drop of glacial acetic acid is added. The mixture is kept hot for 10 min (Step 78). The solution is cooled, and the hydrazone is collected by filtration. 
       123  I!-1-Amino-4-iodo-cyclohex-2-ene-1-carboxylic acid 98 
     Aqueous 3% hydrogen peroxide is added to a mixture of sodium   125  I!iodide, hydrazone 96, and 0.1N HCl in a sealed vial protected by a charcoal vent (Step 79). The reaction is allowed to proceed for 30 min at ambient temperature, quenched with a solution of sodium bisulfite (300 mg/mL). Deprotection of 97 (Step 80) is achieved by using 1 mL of 4N HCl at 115° C. for 15 min and then the aqueous solution is passed through an ion-retardation resin (AG 11A8 50-100 mesh). 
     EXAMPLE 17 
     Synthesis of E-  123  I!-1-Amino-3-(2-iodoethenyl)cyclohexane-1-carboxylic acid 
     1-t-Butyl carbamate-4-bromo-1-cyclohexane-1-carboxylic acid methyl ester 99 
     Bromine is added to a mixture of alcohol 46 and triphenylphosphine in DMF at -10° C. (Step 81). After stirring for 1 h, the mixture is diluted with water and extracted with ether. The ether layer is washed with water, 10% sodium sulfite, and then dried. The ether is removed and the residue is chromatographed on silica gel. 
     1-t-Butyl carbamate-4-ethynyl-1-cyclohexane-1-carboxylic acid methyl ester 100 
     The bromo compound 99 in THF is added to a suspension of lithium acetylide ethylenediamine complex in THF stirred at 0° C. under a nitrogen atmosphere (Step 82). The mixture is stirred for 3 h at 25° C., poured into ice water, and extracted with ether. The ether extract is washed with ice cold 1N HCl, brine and then dried. The ether is removed and the residue is chromatographed on silica gel. 
     1-t-Butyl carbamate-4-((E)-2-tributylstannylethenyl)-1-cyclohexane-1-carboxylic acid methyl ester 101 
     Tributyltin hydride, the alkyne 100 and azobisisobutyronitrile are refluxed in toluene under nitrogen atmosphere for 10 h (Step 83). The reaction mixture is cooled, solvent removed in vacuo, and the residue chromatographed on silica gel. 
       123  I!-1-Amino-4-((E)-2-iodoethenyl)cyclohexane-1-carboxylic acid 102 
     Aqueous 3% hydrogen peroxide is added to a mixture of sodium   123  I!iodide, tributylstannyl 101, and 0.1N HCl in a sealed vial protected by a charcoal vent (Step 84). The reaction is allowed to proceed for 30 min at ambient temperature, quenched with a solution of sodium bisulfite (300 mg/mL). Deprotection (Step 85) is achieved by using 1 mL of 4N HCl at 115° C. for 15 min and then the aqueous solution is passed through an ion-retardation resin (AG 11A8 50-100 mesh). 
     EXAMPLE 18 
     Synthesis of   123  I!-1-Amino-4-(iodomethylenyl)cyclohexane-1-carboxylic acid 
     1-t-Butyl carbamate-4-(bromomethylenyl)-1-cyclohexane-1-carboxylic acid methyl ester 103 
     The phosphonium salt 70 is suspended in ether and ethereal phenyllithium is added rapidly at 25° C. An orange-yellow solution results which becomes mustard yellow within 2 h. To this solution is added protected ketone 95 and the reaction mixture is heated at reflux for 8 h with stirring (Step 86). The ether is removed and the residue is chromatographed on silica gel. 
     1-t-Butyl carbamate-4-(tributylstannylmethylenyl)-1-cyclohexane-1-carboxylic acid methyl ester 104 
     To a solution of 103 in ether at -78° C. is added t-butyllithium (2 eq.) after 15 min tributyltin chloride is added and the mixture is warmed to 25° C. (Step 87). The reaction mixture is poured into ice water and the ether layer separated and dried. The ether is removed and the residue is chromatographed on silica gel. 
       123  I!-1-Amino-4-(iodomethylenyl)cyclohexane-1-carboxylic acid 106 
     Aqueous 3% hydrogen peroxide will be added to a mixture of sodium   125  I!iodide, tributylstannyl 104, and 0.1N HCl in a sealed vial protected by a charcoal vent (Step 88). The reaction is allowed to proceed for 30 min at ambient temperature, quenched with a solution of sodium bisulfite (300 mg/mL). Deprotection of 105 (Step 89) is achieved by using 1 mL of 4N HCl at 115° C. for 15 min and then the aqueous solution is passed through an ion-retardation resin (AG 11A8 50-100 mesh). 
     EXAMPLE 19 
     Biodistribution Studies in Tumor Bearing Rats 
     The distribution of radioactivity expressed as percent dose per gram in tissues of unfasted male fisher rats with implanted gliosarcoma at 5 min and 60 min after intravenous administration of   18  F!FACBC is shown in Table I. The initial level of accumulation of radioactivity in the brain after injection of   18  F!FACBC was low (0.11% dose/gram) at 5 min and increased slightly to 0.26% dose/gram. The agent, however, exhibited a high uptake in the brain tumor. The tumor uptake exhibited a maximum at 60 min (1.72% dose/gram) resulting in an increase in the tumor to brain ratio of 5.58 at 5 min to 6.61 at 60 min. The bone radioactivity showed no increase from 0.52% dose/gram at 5 min, to 0.38% dose/gram at 60 min, which demonstrates the expected stability of the 2-cyclobutyl group to significant in vivo defluorination. 
     We compared the tumor uptake of   18  F!FACBC with   18  F!2-FDG in a separate group of male fisher rats with implanted gliosarcoma at 5 min and 60 min after intravenous administration of   18  F!2-FDG the initial level of accumulation of radioactivity in the brain tumor after injection of   18  F!2-FDG was good, 1.29% dose/gram. The 2-FDG, however, exhibited a decrease in uptake in the brain tumor to 1.05% dose/gram at 60 min. The decrease of radioactivity in the tumor at 60 min in conjunction with initial high brain uptake and retention resulted in a low tumor to brain ratio of 0.84 at 60 min. 
     
                       TABLE I______________________________________Distribution of Radioactivity in Tissues of Unfasted MaleFisher Rats following Intravenous Administration of  .sup.18 F!FACBC         Mean % Injected         Dose/Gram         (Average of 4 Rats)Organ           5 min  60 min______________________________________Blood           0.58   0.32Heart           0.70   0.56Muscle          0.27   0.41Lung            1.13   0.64Kidney          1.08   0.60Spleen          1.55   0.68Liver           1.10   1.70Testis          0.25   0.28Bone            0.52   0.38Brain (B)       0.11   0.26Tumor (T)       0.61   1.72T/B             5.58   6.61______________________________________ 
    
     This significant tumor to brain ratio of 6.6 at 60 min strongly supports the use of   18  F!FACBC as a valuable imaging agent for the diagnosis and management of treatment of metastatic disease in humans by PET. 
     In addition   18  F!FACBC displayed highly specific binding to human astrocyte tumor cells in a human patient, further establishing the suitability of At-labelled compounds of the invention for therapy. 
     EXAMPLE 20 
     Synthesis of  Tc-99m! technetium,  3-(1-(5-mercaptopent-1-ynyl))-1-aminocyclobutane-1-carboxylic acid)! 2.2&#39;methylimino)bis  ethanethiolato!!(2)-N,S,S&#39;!oxo 114 
     1-t-Butyl carbamate-3-(5-chloropent-1-ynyl)cyclobutane-1-carboxylic acid methyl ester 107 
     5-Chloropent-1-yne is cooled to -78° C. and treated with one equivalent of n-butyllithium. 1-t-Butyl carbamate-3-(trifluoromethane sulfonoxymethyl)-cyclobutane-1-carboxylic acid methyl ester (11) is added to the resultant lithium acetylide, the mixture is allowed to warm to room temperature, poured onto ice and extracted with ether. The solvent is removed and the product is purified by column chromatography (silica gel). 
     1-t-Butyl carbamate-3-(1-(5-mercaptopent-1-ynyl))cyclobutane-1-carboxylic acid methyl ester 110 
     Thiourea and 1-t-butyl carbamate-3-(5-chloropent-1-ynyl)cyclobutane-1-carboxylic acid methyl ester (107) are heated together at 80° C. in DMF for one hour. The reaction intermediate is hydrolyzed by warming to 50° C. with 3M aqueous hydroxide. The mixture is neutralized with dilute HCl, extracted with ether and the combined ether extract is washed with brine and dried (MgSO 4 ). Solvent is removed to give the mercaptan product 110. 
      Tc-99m! Technetium,  3-(1-(5-mercaptopent-1-ynyl))-1-aminocyclobutane-1-carboxylic acid)! 2,2&#39;-methylimino)bis  ethanethiolato!!(2-)N,S,S&#39;!oxo 114 
     The complex is prepared by combining  99m  TcO 4  -eluate and equimolar amounts of N-di(2-ethylmercapto)methylamine and 1-t-butyl carbamate-3-(5-mercaptopent-1-ynyl)cyclobutane-1-carboxylic acid methyl ester (110). The mixture is applied to a C-18 Seppak and eluted with 0.5 mL of water and the 0.5 mL ethanol to obtain the protected  99mTc! amino acid. This compound is hydrolyzed with 3N HCl at 120° C. for 20 min and then purified by passage through AG11-8A ion retardation resin. ##STR15## 
     EXAMPLE 21 
     Synthesis of  Tc-99m! technetium,  3-(1-(5-mercaptopent-1(Z)-enyl))-1-aminocyclobutane-1-carboxylic acid)! 2,2&#39;-methylimino)bis  ethanethiolato!!(2)-N,S,S&#39;!oxo 123 
     1-t-Butyl carbamate-3-(1-(5-chloropent-1(Z)-enyl))-cyclobutane-1-carboxylic acid methyl ester 117 
     A mixture of 1-t-butyl carbamate-3-(1-5-chloropent-1-ynyl))cyclobutane-1-carboxylic acid methyl ester (107), palladium on barium sulfate, quinoline and methanol are shaken under hydrogen for 8 h. The catalyst is removed by filtration through Celite and washed with methanol. The filtrate is concentrated under reduced pressure to give the cis-alkene compound 120. 
     1-t-Butyl carbamate-3-(1-(5-mercaptopent-1(Z)-enyl))-cyclobutane-1-carboxylic acid methyl ester 117 
     Thiourea and 1-t-butyl carbamate-3-(1-5-chloropent-1(Z)-enyl))-cyclobutane-1-carboxylic acid methyl ester (117) are heated together at 80° C. in DMF for one hour. The reaction intermediate is hydrolyzed by warming to 50° C. with 3M aqueous hydroxide. The mixture is neutralized with dilute HCl, extracted with ether and the combined ether extract is washed with brine and dried (MgSO 4 ). Solvent is removed to give the mercaptan product 120. 
      Tc-99m! Technetium,  3-(1-(5-mercaptopent-1(Z)-enyl)-1-aminocyclobutane-1-carboxylic acid)! 2,2&#39;-methyl-imino) bis ethanethiolato!!(2-)N,S,S&#39;!oxo 123 
     The complex is prepared by combining  99m  TcO 4  -eluate and equimolar amounts of N-di(2-ethylmercapto)methylamine and 1-t-butyl carbamate-3-(1-(5-mercaptopent-1(Z)-enyl))cyclobutane-1-carboxylic acid methyl ester (120). The mixture is applied to a C-18 Seppak and eluted with 0.5 mL of water and then 0.5 mL ethanol to obtain the protected  99mTc! amino acid. This compound is hydrolyzed with trifluoroacetic acid (TFA) at 25° C. for 5 min and then purified by passage through AG11-8A ion retardation resin. ##STR16## 
     EXAMPLE 22 
     Synthesis of  Tc-99m!technetium,  3-(5-(1-pentanethiol))-1-aminocyclobutane-1-carboxylic acid)! 2,2&#39;-methylimino)bis  ethanethiolato!!(2)-N,S,S&#39;oxo 132 
     1-t-Butyl carbamate-3-(5-(1-chloropentyl))-cyclobutane-1-carboxylic acid methyl ester 126 
     A mixture of 1-t-butyl carbamate-3-(1-(5-chloropent-1-ynyl))cyclobutane-1-carboxylic acid methyl ester (107), Raney Ni and methanol are shaken under hydrogen for 8 h. The catalyst is removed by filtration through Celite and washed with methanol. The filtrate is concentrated under reduced pressure to give the saturated chloroalkane compound 126. The solvent is removed and the product is purified by column chromatography (silicia gel). 
     1-t-Butyl carbamate-3-(5-(1-pentanethiol))cyclobutane-1-carboxylic acid methyl ester 129 
     Thiourea and 1-t-butyl carbamate-3-(1-5-chloropent-1(Z)-enyl))-cyclobutane-1-carboxylic acid methyl ester (126) are heated together at 80° C. in DMF for one hour. The reaction intermediate is hydrolyzed by warming to 50° C. with 3M aqueous hydroxide. The mixture is neutralized with dilute HCl, extracted with ether and the combined ether extract is washed with brine and dried (MgSO 4 ). Solvent is removed to give the mercaptan product 129. 
      Tc-99m! Technetium,  3-(5-(1-pentanethiol))-1-aminocyclobutane-1-carboxylic acid)! 2,2&#39;-methyl-imino)bis ethanethiolato!! (2)N,S,S&#39;!oxo 132 
     The complex is prepared by combining  99m  TcO 4  -eluate and equimolar amounts of N-di(2-ethylmercapto)methylamine and 1-t-butyl carbamate-3-(5-(1-pentanethiol))cyclobutane-1-carboxylic acid methyl ester (129). The mixture is applied to a C-18 Seppak and eluted with 0.5 mL of water and then 0.5 mL ethanol to obtain the protected  99mTc! amino acid. This compound is hydrolyzed with TFA at 25° C. for 5 min and then purified by passage through AG11-8A ion retardation resin. ##STR17## 
     EXAMPLE 23 
     Synthesis of  Tc-99m! technetium,  3-(1-(5-mercaptopent-1(E)-enyl))-1-aminocyclobutane-1-carboxylic acid)! 2,2&#39;-methylimino) bis  ethanethiolato!!(2)-N.S.S&#39;!oxo 141 
     1-t-Butyl carbamate-3-(1-(5-chloropent-1(E)-enyl))cyclobutane-1-carboxylic acid methyl ester 135 
     5-Chloro-1(E)-iodepent-1-ene in ether is cooled to -78° C. and treated with n-butyllithium. After stirring for one hour, 1-t-butyl carbamate-3-(trifluoromethane sulfonoxymethyl)-cyclobutane-1-carboxylic acid methyl ester (11) is added to the lithium alkynylide over a 15 min period. The mixture is stirred at 25° C. for 1 h poured into ice cold aqueous 5% HCl and extracted with ether. The solvent is removed and the product is purified by column chromatography (silica gel). 
     1-t-Butyl carbamate-3-(1-(5-mercaptopent-1(E)-enyl))cyclobutane-1-carboxylic acid methyl ester 138 
     Thiourea and 1-t-butyl carbamate-3-(1-(5-chloropent-1(E)-enyl))-cyclobutane-1-carboxylic acid methyl ester (135) are heated together at 80° C. in DMF for one hour. The reaction intermediate is hydrolyzed by warming to 50° C. with 3M aqueous hydroxide. The mixture is neutralized with dilute HCl, extracted with ether and the combined ether extract is washed with brine and dried (MgSO 4 ). Solvent is removed to give the mercaptan product 138. 
      Tc-99m! technetium,  3-(1-(5-mercaptopent-1(E)-enyl))-1-aminocyclobutane-1-carboxylic acid)! 2,2&#39;-methyl-imino) bis ethanethiolato!!(2-)N,S,S&#39;!oxo 141. 
     The complex is prepared by combining  99m  TcO 4  -eluate and equimolar amounts of N-di(2-ethylmercapto)methylamine and 1-t-butyl carbamate-3-(1-(5-mercaptopent-1(E)-enyl))cyclobutane-1-carboxylic acid methyl ester (138). The mixture is applied to a C-18 Seppak and eluted with 0.5 mL of water and then 0.5 mL ethanol to obtain the protected  99mTc! amino acid. This compound is hydrolyzed with TFA at 25° C. for 5 min and then purified by passage through AG11-8A ion retardation resin. ##STR18## 
     EXAMPLE 24 
     Synthesis of  99mTc! technetium,  3-(1-(5-aminopent-1-ynyl))-1-aminocyclobutane-1-carboxylic acid)carbonyl cyclopentadienyl! tricarbonyl!150 
     1-t-Butyl carbamate-3-(1-(5-aminopent-1-ynyl))cyclobutane-1-carboxylic acid methyl ester 144 
     General procedure 
     1-t-Butyl carbamate-3-(1-(5-aminopent-1-ynyl))cyclobutane-1-carboxylic acid methyl ester (107) is reacted with sodium azide in DMF at 80° C. The mixture is quenched with water and extracted with ether to afford the azide. The crude azide product is dissolved in methanol and treated with sodium borohydride and quenched with cold 1M HCl. The mixture is brought to a pH of 8 and extracted with ether to give the amine product 144. 
      99mTc! Technetium,  3-(1-(5-aminopent-1-ynyl))-1-aminocyclobutane-1-carboxylic acid)carbonyl cyclopentadienyl! tricarbonyl! 150 
     General procedure 
     A solution of ferrocenedicarbonyl chloride, the amino compound 144 and triethylamine in dry methylene chloride are heated at reflux for 2 h. The solution is extracted methylene chloride, washed with saturated sodium bicarbonate and evaporated to dryness. 
     The ferrocene compound 147 and Mn(CO)5Br are placed in a glass tube, and THF and  99m  TcO 4  -eluate are added. The glass tube is sealed and heated at 150° C. for 1 h. The mixture is applied to a C-18 Seppak and eluted with 0.5 mL of water and then 0.5 mL ethanol to obtain the protected  99mTc! amino acid. This compound is hydrolyzed with TFA at 25° C. for 5 min and then purified by passage through AG11-8A ion retardation resin. ##STR19## 
     EXAMPLE 25 
     Synthesis of  99mTc! technetium,  3-(1-(5-aminopent-1(Z)-enyl))-1-aminocyclobutane-1-carboxylic acid)carbonyl cyclopentadienyl! tricarbonyl! 159 
     1-t-Butyl carbamate-3-(1-(5-aminopent-1(Z)-enyl)-cyclobutane-1-carboxylic acid methyl ester 153 
     The above procedure for 144 is followed using 1-t-butyl carbamate-3-(1-(5-aminopent-1(Z)-enyl)cyclobutane-1-carboxylic acid methyl ester (144) 
      99mTc! Technetium,  3-(1-(5-aminopent-1(Z)-enyl))-1-aminocyclobutane-1-carboxylic acid)carbonyl cyclopentadienyl! tricarbonyl! 159 
     The above procedure for 150 is followed using 1-t-butyl carbamate-3-(1-(5-aminopent-1(Z)-enyl-cyclobutane-1-carboxylic acid methyl ester (153) as the amino compound. ##STR20## 
     EXAMPLE 26 
     Synthesis of  99mTc! technetium,  3-(1-(5-pentaneamine))-1-aminocyclobutane-1-carboxylic acid)carbonyl cyclopentadienyl! tricarbonyl! 168 
     1-t-Butyl carbamate-3-(5-(1-pentylamine))cyclobutane-1-carboxylic acid methyl ester 162 
     The above procedure for 144 is followed using 1-t-butyl carbamate-3-(5-(1-chloropentyl))cyclobutane-1-carboxylic acid methyl ester (126). 
      99mTc! technetium,  3-(1-(5-pentaneamine))aminocyclobutane-1-carboxylic acid)carbonyl cyclopentadienyl! tricarbonyl! 168 
     The above procedure for 150 is followed using 1-t-butyl carbamate-3-(5-(1-pentylamine))cyclobutane-1-carboxylic acid methyl ester (162) as the amino compound. ##STR21## 
     EXAMPLE 27 
     Synthesis of  99mTc! technetium,  3-(1-(5-aminopent-1(E)-enyl))-1-aminocyclobutane-1-carboxylic acid)carbonyl cylclopentadienyl)  tricarbonyl! 177. 
     1-t-Butyl carbamate-3-(1-(5-aminopent-1(E)-enyl))cyclobutane-1-carboxylic acid methyl ester 162. 
     The above procedure for 144 is followed using 1-t-butyl carbamate-3-(1-(5-aminopent-1(E)-enyl))cyclobutane-1-carboxylic acid methyl ester (135). 
      99mTc! Technetium,  3-(1-(5-aminopent-1(E)-enyl))-1-aminocyclobutane-1-carboxylic acid)carbonyl cyclopentadienyl! tricarbonyl! 177 
     The above procedure for 150 is followed using 1-t-butyl carbamate-3-(1-(5-aminopent-1(E)-enyl)-cyclobutane-1-carboxylic acid methyl ester 171 as the amino compound. ##STR22## 
     EXAMPLE 28 
     Synthesis of  99mTc! Technetium, bis 3-(1-(5N-aminopent-1-ynyl)-6-hydrazinonicotinamide)-1-aminocyclobutane-1-carboxylic acid!183 
     1-t-Butyl carbamate-3-(1-(5-aminopent-1-ynyl))cyclobutane-1-carboxylic acid methyl ester (144) is added to a solution of succinimidyl-6-t-Boc-hydrazinopyridine-3-carboxylic acid and diisopropylethylamine in DMF. The mixture is stirred for 2 h, water is added and the mixture is extracted with ether. The t-Boc and methyl protecting groups are removed by stirring the crude product with 5 ml of trifluoroacetic acid (TFA). The TFA is removed by rotary evaporation and the product (180) is purified by reverse phase HPLC. 
     The following procedure is used to radiolabel the HYNIC amino acid analogs with  99m  Tc. A solution of the Hynic amino acid 171, DMSO, 0.1M acetate buffer pH 5.2 and 99mTc-glucoheptonate are vortexed briefly and then the mixture is allowed to stand for 1 h. The labeled compound 174 is purified by reverse phase HPLC. 
     Synthesis of  99mTc! technetium, bis 3-(1-(5N-aminopent-1(Z)-enyl-6-hydrazinonicotinamide)-1-aminocyclobutane-1-carboxylic acid! 189 
     The above procedure for 183 is followed using 1-t-butyl carbamate-3-(1-(5-aminopent-1(Z)-enyl))cyclobutane-1-carboxylic acid methyl ester (153) as the amino compound. 
     Synthesis of  99mTc! technetium, bis 3-(1-(5N-aminopentyl)-6-hydrazinonicotinamide)-1-aminocyclobutane-1-carboxylic acid! 195 
     The above procedure for 183 is followed using 1-t-butyl carbamate-3-(5-(1-pentylamine))cyclobutane-1-carboxylic acid methyl ester (153) as the amino compound. 
     Synthesis of  99mTc! technetium, bis  3-(1-(5N-aminopent-1(E)-enyl)-6-hydrazinonicotinamide)-1-aminocyclobutane-1-carboxylic acid! 201 
     The above procedure for 183 is followed using 1-t-butyl carbamate-3-(1-(5-aminopent-1(E)-enyl))cyclobutane-1-carboxylic acid methyl ester (171) as the amino compound. ##STR23##