5-(2-iodovinyl)-2--deoxyuridine and Herpes-Simplex

The blood-brain barrier penetration of a radiohalogenated (125I) derivative of the antiviral drug (E)-5-(2-iodovinyl)-2'-deoxyuridine (IVDU) was investigated in a rat model of herpes encephalitis. CNS delivery was assessed by external gamma camera scintigraphic imaging in vivo, a technique which may have general application in evaluating brain specific delivery of drugs, and by autoradiography of cryostat sections of rat brain. Radiohalogenated IVDU was found to be almost totally excluded from the CNS. These findings may be explained in terms of the poor lipid solubility of IVDU (in vitro oil/aqueous salt solution partition coefficient 0.012). Since IVDU appears in CSF after carotid artery administration, our results stress the necessity, in the design of compounds for the treatment of CNS infections, of distinguishing blood-brain, blood-CSF, and CSF-brain drug barriers. The significance of our data both in relation to the development of neuro-radiological diagnosis and antiviral chemotherapy of CNS infection is discussed.

Topics: Animals; Antiviral Agents; Autoradiography; Blood-Brain Barrier; Brain; Chemical Phenomena; Chemistry, Physical; Chromatography, Thin Layer; Encephalitis; Herpes Simplex; Idoxuridine; Iodine Radioisotopes; Radionuclide Imaging; Rats; Simplexvirus

Liposomal encapsulation of radioiodinated anti-herpes nucleosides was undertaken to reduce metabolic inactivation and increase blood-brain barrier penetration of the nucleosides, and so provide formulations suitable for use in the non-invasive scintigraphic diagnosis of herpes simplex encephalitis (HSE). The nucleosides investigated were [125I]-IVdU and its more lipophilic 3-methyl derivative, and they were encapsulated in phosphatidylcholine:cholesterol:sulfatide liposomes with an efficiency of 4.4% and 1.7% respectively. The encapsulation of IVdU reduced in vitro phosphorolysis (by 31% in serum at 25 degrees C over 3 hr as compared with non-encapsulated IVdU), and markedly increased in vivo stability (fifty-fold greater than that of free drug). In normal mice, higher radioactivity levels were observed in most tissues and there was prolonged, constant blood and brain uptake. Biodistribution of liposomal IVdU in herpes simplex virus (HSV) infected animals was similar, but somewhat lower concentrations were attained. Liposomal encapsulation of [125I]-3-CH3-IVdU produced less dramatic changes in tissue distribution in either healthy or HSV infected mice, as compared with the non-encapsulated drug. Whilst, in HSV infected mice, liposomal encapsulation of both drugs caused increased uptake by spleen, liver and lung, the uptake by brain was still too low for detection by whole-body scintigraphy.

Topics: Animals; Blood-Brain Barrier; Cholesterol; Drug Stability; Encephalitis; Herpes Simplex; Idoxuridine; Iodine Radioisotopes; Liposomes; Male; Mice; Mice, Inbred Strains; Phosphatidylcholines; Simplexvirus; Sulfoglycosphingolipids; Temperature

The potential of utilizing a radio-labelled derivative of the antiviral drug (E)-5-(2-iodovinyl)-2'-deoxyuridine (IVDU) for the specific, non-invasive, in vivo diagnosis of Herpes simplex virus encephalitis (HSVE) was investigated in a rat model of the disease. Following pharmacological disruption of the blood brain barrier radiolabelled IVDU was administered by intra-carotid injection. Brain radioactivity was compared between control and infected animals via gamma camera scintigraphy. After clearance of non-metabolized drug, markedly higher levels of activity were found in infected brain. Post-mortem studies of cryostat sections of brain examined by autoradiography and immunochemical staining showed the radioactivity selectively accumulated in areas of virus infection. These results indicate that radio-labelled derivatives of antiviral drugs may allow the specific neuro-radiological diagnosis of HSVE.

Topics: Animals; Antiviral Agents; Autoradiography; Blood-Brain Barrier; Brain; Carotid Arteries; Encephalitis; Etoposide; Female; Herpes Simplex; Idoxuridine; Injections, Intra-Arterial; Iodine Radioisotopes; Isotope Labeling; Radionuclide Imaging; Rats; Vero Cells

The synthesis of [125I]-(E)-5-(2-iodovinyl)-2'-deoxyuridine [( 125I]IVDU) by a halogen isotope exchange reaction has been monitored in various reaction conditions. Quantitative incorporation of radioiodine into IVDU was obtained within 20 min by a simple and safe method that is suitable for application in any nuclear medicine laboratory. The radiolabelled antiviral agent can be used without further purification.

Topics: Antiviral Agents; Encephalitis; Herpes Simplex; Humans; Idoxuridine; Iodine Radioisotopes; Radiochemistry; Radionuclide Imaging

E-5-(2-Iodovinyl)-2'-deoxyuridine (IVdU) is a potent inhibitor of herpes simplex virus type 1 replication in vitro. The selective antiviral activity of IVdU is due to preferential phosphorylation by the herpes simplex virus type 1-encoded thymidine kinase. This selective sequesteration provided the rationale for the development of radioiodinated IVdU as a potential radiopharmaceutical compound for use in noninvasive diagnosis of herpes simplex virus encephalitis. We studied the pharmacokinetics and the in vivo metabolism of [131I]IVdU in dogs. The radioactive components in plasma were characterized and quantitated by radio high-pressure liquid chromatography. During incubation with dog blood, [131I]IVdU was metabolized to the corresponding base (E)-5-(2-iodovinyl)uracil. 131I-labeled (E)-5-(2-iodovinyl)uracil accounted for 73% of the total radioactivity present in plasma after 2 h of incubation, suggesting that phosphorolysis of the nucleoside is the major degradation pathway of IVdU in blood. The in vivo studies showed that there was an initial rapid clearance of the tracer from blood, followed by a second very slow clearance phase. Evaluation of the renal excretion of the radiotracer showed that only 8% of the injected dose was excreted by kidneys over an 8-h period. IVdU was rapidly metabolized to three radioactive compounds. Two of these metabolites, the base (E)-5-(2-iodovinyl)uracil and iodide, were characterized. The radioactivity associated with these metabolites was responsible for the slow clearance phase. Our results suggest that the development of [131I]IVdU as a radiopharmaceutical compound will require measures to prevent its rapid degradation in vivo.

Topics: Animals; Chromatography, High Pressure Liquid; Dogs; Encephalitis; Herpes Simplex; Idoxuridine; Iodine Radioisotopes; Kinetics

The carbocyclic analogues of the potent and selective antiherpes agents (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU), (E)-5-(2-iodovinyl)-2'-deoxyuridine (IVDU), and (E)-5-(2-bromovinyl)-2'-deoxycytidine (BVDC) were synthesized by conventional methods with use of carbocyclic 2'-deoxyuridine as starting material. C-BVDU, C-IVDU, and C-BVDC were equally selective, albeit slightly less potent, in their antiherpes action than BVDU, IVDU, and BVDC. Although resistant to degradation by pyrimidine nucleoside phosphorylases, C-BVDU did not prove more effective than BVDU in the systemic (oral, intraperitoneal) or topical treatment of HSV-1 infections in mice.

Topics: Animals; Antineoplastic Agents; Antiviral Agents; Bromodeoxyuridine; Cell Division; Cell Line; Cyclopentanes; Cytopathogenic Effect, Viral; Deoxycytidine; Deoxyuridine; Herpes Simplex; Humans; Mice; Mice, Hairless; Rabbits; Rats; Simplexvirus; Vaccinia virus; Vesicular stomatitis Indiana virus; Virus Cultivation

Radiohalogenated (E)-5-(2-iodovinyl)-2'-deoxyuridine (IVDU, 4) and (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU, 5) were synthesized by reaction of (E)-5-(2-carboxyvinyl)-2'-deoxyuridine (1) with radiolabelled iodide or bromide in the presence of chloramine-T. A "no-carrier-added" synthesis of [131I]IVDU was completed within 30 min providing a radiochemical yield of 65%. Alternatively, radioactive iodine was incorporated into IVDU using a halogen isotope exchange reaction catalyzed by cuprous ion. [82Br]BVDU was also prepared by direct neutron activation of unlabelled BVDU.

Topics: Antiviral Agents; Bromine; Bromodeoxyuridine; Encephalitis; Herpes Simplex; Humans; Idoxuridine; Iodine Radioisotopes; Isotope Labeling; Radioisotopes; Radionuclide Imaging

We have synthesized a 131I-radiolabeled antiviral compound (E)-5-(2-iodovinyl)-2'-deoxyuridine (IVdU) and shown that this agent was selectively trapped within rabbit kidney cells, infected in vitro by thymidine kinase-positive (TK+) herpes simplex virus (HSV). The uptake of 131I-labeled IVdU was specific, as it was not concentrated within either HSV (TK-) or mock-infected cells. In certain conditions, over 40% of the radiolabel was selectively trapped within HSV (TK+)-infected cells. This was a 20- to 30-fold increase over the uptake of 131I-labeled IVdU by HSV (TK-) or mock-infected cells. The uptake of 131I-labeled IVdU varied directly with (i) the dose of the virus used to infect the rabbit kidney cells; (ii) the concentration of radiolabeled IVdU added to the system; and (iii) the time of exposure of IVdU to infected cells. The ability of this agent to be trapped within HSV (TK+)-infected cells merits further evaluation in animal models as it has potential as a noninvasive, herpes-specific diagnostic test, in particular for HSV encephalitis.

Topics: Animals; Colony-Forming Units Assay; Herpes Simplex; Idoxuridine; Iodine Radioisotopes; Isotope Labeling; Kidney; Rabbits; Thymidine Kinase; Time Factors; Virus Cultivation