Synthesis of a novel bifunctional chelator AmBaSar based on sarcophagine for peptide conjugation and (64)Cu radiolabelling.

Copper-64 shows promise as both a suitable PET imaging and therapeutic radionuclide due to its nuclear characteristics. Stable attachment of radioactive (64)Cu(2+) to targeted imaging probes requires the use of a bifunctional chelator. Sarcophagine (Sar) ligands coordinate the metal ion (64)Cu(2+) within the multiple macrocyclic rings comprising the cage structure, yielding extraordinarily stable complexes that are inert to dissociation of the metal ion in vivo.

In vivo measurement of cell proliferation in canine brain tumor using C-11-labeled FMAU and PET.

Introduction: Noncatabolized thymidine analogs are being developed for use in imaging DNA synthesis. We sought to relate a labeling index measured by immunohistochemical staining bromodeoxyuridine (BUdR) technique to the uptake of (11)C 2'-fluoro-5-methyl-1-beta-d-arabinofuranosyluracil (FMAU) measured with positron emission tomography (PET) in a brain tumor model.

Methods: Adult beagles (n=8) with implanted brain tumors received [(11)C]FMAU and dynamic imaging with arterial sampling.

Biodistribution and PET imaging of [(18)F]-fluoroadenosine derivatives.

Introduction: Many fluorinated analogues of adenosine nucleoside have been synthesized and studied as potential antitumor and antiviral agents. Earlier, we reported radiosynthesis of 2'-deoxy-2'-[(18)F]fluoro-1-beta-D-arabinofuranosyl-adenine ([(18)F]-FAA) and 3'-deoxy-3'-[(18)F]fluoro-1-beta-d-xylofuranosyl-adenine ([(18)F]FXA). Now, we report their in vivo studies including blood clearance, biodistribution and micro-PET imaging in tumor-bearing nude mice.

Pharmacokinetics of the thymidine analog 2'-fluoro-5-methyl-1-beta-D-arabinofuranosyluracil (FMAU) in tumor-bearing rats.

The thymidine analog 2'-fluoro-5-methyl-1-beta-D-arabinofuranosyluracil (FMAU) is incorporated into DNA and is resistant to catabolism. We performed pharmacokinetic measurements with [(14)C]FMAU and PET studies with [(11)C]FMAU using rats bearing several different syngeneic tumors. Among normal tissues, FMAU uptake reflected relative cell turnover rates.

Synthesis of 2'-deoxy-2'-[18F]fluoro-5-bromo-1-beta-D-arabinofuranosyluracil ([18F]-FBAU) and 2'-deoxy-2'-[18F]fluoro-5-chloro-1-beta-D-arabinofuranosyl-uracil ([18F]-FCAU), and their biological evaluation as markers for gene expression.

[(18)F]-FBAU and [(18)F]-FCAU have been synthesized and evaluated in vivo as markers for HSV1-tk gene expression. At 2 hours, uptake of [(18)F]-FBAU and [(18)F]-FCAU in HSV1-tk-positive tumors was 7.9-fold and 6.

Kinetic modeling of 5-fluorouracil anabolism in colorectal adenocarcinoma: a positron emission tomography study in rats.

Drug uptake and anabolism by tumors are prerequisites of response to 5-fluorouracil (5-FU). Positron emission tomography (PET) with 5-[(18)F]FU (PET/5-[(18)F]FU) is potentially useful for noninvasive measurement of these processes, but is severely hampered by rapid catabolism of 5-[(18)F]FU in vivo. This study explored the combined use of PET/5-[(18)F]FU and eniluracil (5-ethynyluracil), a potent inhibitor of 5-FU catabolism, to measure the pharmacokinetics of 5-FU uptake and metabolism in tumors.

Blocking catabolism with eniluracil enhances PET studies of 5-[18F]fluorouracil pharmacokinetics.

Unlabelled: Noninvasive methods for measuring the pharmacokinetics of chemotherapeutic drugs such as 5-fluorouracil (FU) are needed for individualized optimization of treatment regimens. PET imaging of [18F]FU (PET/[18F]FU) is potentially useful in this context, but PET/[18F]FU is severely hampered by low tumor uptake of radiolabel and rapid catabolism of FU in vivo. Pretreatment with eniluracil (5-ethynyluracil) prevents catabolism of FU.

Synthesis of 2'-fluoro-5-[11C]-methyl-1-beta-D-arabinofuranosyluracil ([11C]-FMAU): a potential nucleoside analog for in vivo study of cellular proliferation with PET.

Rapid in vivo catabolism limits the use of currently available radiotracers used in tumor proliferation studies with PET. This is manifested by the need to develop complex mathematical models to interpret kinetic and metabolite data obtained from imaging studies with agents such as carbon-11 labeled thymidine. A potential carbon-11 labeled radiotracer for cellular proliferation, 2'-fluoro-5-([11C]-methyl)-1-beta-D-arabinofuranosyluracil (FMAU), has been prepared using a previously described method for preparation of [11C]methyl-thymidine where selective alkylation of a pyrimidyl dianion is accomplished with [11C]methyl iodide at the 5-position of the pyrimidine ring.

In-vivo identification of tumor multidrug resistance with 3H-colchicine [corrected].

Multidrug resistance (MDR) is a major obstacle in the clinical treatment of cancer with natural-product anticancer agents. Identification of MDR in vivo could be important in the design of chemotherapeutic regimens. As a first step in developing radiolabeled drugs to detect MDR, we measured the in vivo distribution of radiolabel from [ring C, methoxy-3H]-colchicine ([3H]-CHC) in immunosuppressed mice bearing xenografts of colchicine-resistant and sensitive tumor cell lines.

Tumor imaging with carbon-11 labeled alpha-aminoisobutyric acid (AIB) in patients with malignant melanoma.

The potential usefulness of [C-11]-labeled alpha-aminoisobutyric acid (AIB) for tumor imaging has been demonstrated previously in our findings of increased tumor uptake with C-14-labeled AIB in human melanoma heterotransplants in nude mice, and subsequently, in a single case study using C-11 AIB to demonstrate the extent of metastases in patient with widespread malignant melanoma. We report here on the use of C-11 AIB in ten patients with metastatic or unresectable malignant melanoma. Five patients had intense tracer uptake at all known sites of tumor involvement.

Structure and conformation of pseudouridine analogues.

The structural and conformational features of the "anomeric" DL-trans- and DL-cis-5-(3-hydroxytetrahydrofuran-2-yl)uracils (3a, 4a) and five similar analogues were studied in order to determine their applicability as models of beta- and alpha-pseudouridine. The 270-MHz proton NMR spectra were measured for all analogues to define their ring geometries in solution and to estimate the solution population of model N, S conformers in a two-state dynamic equilibrium treatment. Two sets of calculations were employed to evaluate the relative contributions of these states to the observed vicinal coupling constants related to the C(3')-C(4') fragment.

A comparative proton magnetic resonance conformational study of the tRNA "wobble" nucleosides 5-carboxymethyl-, 5-methoxycarbonylmethyl-, and 5-carbamoylmethyl-uridine.

The 270-MHz proton magnetic resonance spectra of 5-carboxymethyluridine, 5-methoxycarbonylmethyluridine, and 5-carbamoylmethyluridine have been obtained, and analyzed iteratively using LAOCOON 3. A standard treatment of the obtained data reveals that in each the 5-substituent produces no significant alteration in the furanose puckers, their equilibrium state, and the relative populations of the gg, tg, and gt exocyclic hydroxymethyl rotamers relative to uridine. The analogous similarity in furanose chemical shifts suggests that these derivatives favor the anti glycosyl state.

A comparative conformational study of certain 2'-deoxy-2'-fluoro-arabinofuranosylcytosine nucleosides.

The 270 MHz proton NMR spectra of 2'-deoxy-2'-fluoro-beta-D-arabinofurano-syl-5-iodocytosine as well as the respective 5-bromo and 5-chloro derivatives have been iteratively analyzed using LAOCOON 3. The derived parameters indicate that the fluorine substituent in an arabino configuration results in an approx. 50 : 50 C(3')-endo C(2')-endo conformer mixture.