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The “classical” positron emitting radionuclides include oxygen-15, nitrogen-13 and carbon-11 which possess unique properties for medical imaging. They are radionuclides of the fundamental elements of biological matter. They each possess short half-lives which allow their use in designed radiotracers for clinical investigations with minimal risk and they are readily able to be produced in sufficient activities by low energy nuclear reactions. At present several accelerator manufacturers offer production packages for these radionuclides emphasizing targetry with consideration of the cyclotron extracted energies for nuclide production and on-line chemistry systems for the continuous production of specific precursors or radiotracers. Following the installation and acceptance of the MSKCC TR 19/9 Cyclotron, our experience with the procured chemistry module for the preparation of oxygen-15 labeled water has forced us to examine the design and the operation of the synthetic unit with a view toward the state of New York’s regulations addressing the environmental pollution from radioactive materials. The chemistry module was refined with subtle modifications to the chemistry procedure/unit and our experience with the unit is presented as an example of our approach to insure regulatory compliance.

Purpose: To compare two potential positron emission tomography (PET) tracers of tumor hypoxia in an animal model. Methods and Materials: The purported hypoxia imaging agents 18F-fluoromisonidazole (FMISO) and 64Cu(II)-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM) were compared by serial microPET imaging of Fisher-Copenhagen rats bearing the R3327-AT anaplastic rat prostate tumor. Probe measurements of intratumoral P o 2 were compared with the image data. At the microscopic level, the relationship between the spatial distributions of 64Cu (assessed by digital autoradiography) and tumor hypoxia (assessed by immunofluorescent detection of pimonidazole) was examined. 18F-FMISO and 64Cu-ATSM microPET images were also acquired in nude rats bearing xenografts derived from the human squamous cell carcinoma cell line, FaDu. Results: In R3327-AT tumors, the intratumoral distribution of 18F-FMISO remained relatively constant 1–4 h after injection. However, that of 64Cu-ATSM displayed a significant temporal evolution for 0.5–20 h after injection in most tumors. In general, only when 64Cu-ATSM was imaged at later times (16–20 h after injection) did it correspond to the distribution of 18F-FMISO. Oxygen probe measurements were broadly consistent with 18F-FMISO and late 64Cu-ATSM images but not with early 64Cu-ATSM images. At the microscopic level, a negative correlation was found between tumor hypoxia and 64Cu distribution when assessed at early times and a positive correlation when assessed at later times. For the FaDu tumor model, the early and late 64Cu-ATSM microPET images were similar and were in general concordance with the 18F-FMISO scans. Conclusion: The difference in behavior between the R3327-AT and FaDu tumor models suggests a tumor-specific dependence of Cu-ATSM uptake and retention under hypoxic conditions.

Signaling through the B cell antigen receptor (BCR) is amplified and prolonged by coligation of the BCR to the CD19/CD21/CD81 coreceptor complex. Coligation is induced during immune responses by the simultaneous binding of complement-tagged antigens to the complement receptor, CD21, and to the BCR. Enhanced signaling is due in part to the ability of the CD19/CD21/CD81 complex to stabilize the BCR in sphingolipid- and cholesterol-rich membrane microdomains termed lipid rafts. The tetraspanin CD81 is essential for the raft-stabilizing function of the coreceptor. Here we show that coligation of the BCR and the CD19/CD21/CD81 complex leads to selective, rapid, and reversible palmitoylation of CD81 and that palmitoylation is necessary for the raft stabilizing function of the CD19/CD21/CD81 complex. Inducible palmitoylation may represent a novel mechanism by which tetraspanins function to facilitate lipid raft-dependent receptor signaling.

Radionuclide labeled somatostatin analogues selectively target somatostatin receptor (SSTR)-expressing tumors as a basis for diagnosis and treatment of these tumors. Recently, a DOTA-functionalized somatostatin analogue, DOTATOC (DOTA-DPhe1-Tyr3-octreotide) has been developed. This compound has been shown to be superior to the other somatostatin analogues as indicated by its uniquely high tumor-to-non-target tissue ratio. DOTATOC can be labeled with a variety of radiometals including gallium radioisotopes. Gallium-66 is a positron emitting radionuclide (T(1/2) =9.5 hr; beta+=56%), that can be produced in carrier free form by a low-beam energy cyclotron. In this study we investigated SSTR targeting characteristics of 66Ga-DOTATOC in AR42J rat pancreas tumor implanted nude mice as a potential agent for diagnosis and receptor-mediated internal radiotherapy of SSTR-expressing tumors. We compared our results with 67Ga- and 68Ga- labeled DOTATOC. The radiolabeling procedure gave labeling yield ranged from 85-95% and radiochemical and chemical purity was > 95%. In-vitro competitive binding curves and in-vivo competitive displacement studies with an excess of unlabeled peptide indicates that there is specific binding of the radioligand to SSTR. Animal biodistribution data and serial microPET images demonstrated rapid tumor uptake and rapid clearance from the blood and all tissues except kidney. Maximum % ID/g values for tumor were 10.0 +/- 0.7, 13.2 +/- 2.1 and 9.8 +/- 1.5 for 66Ga-, 67Ga-, and 68Ga-DOTATOC, respectively. Calculated tumor, kidney and bone marrow doses for 66Ga-DOTATOC based on biodistribution data were 178, 109 and 1.2 cGy/MBq, respectively. We conclude that 66Ga labeled DOTATOC can be used for PET diagnosis and quantitative imaging-based dosimetry of SSTR positive tumors. 66Ga-DOTATOC may also be used in higher doses for ablation of these tumors. However, kidney is the critical organ for toxicity (tumor/kidney ratio = 1.64), and high kidney uptake must be eliminated before devising a therapy protocol.

Background: Hepatectomy represents a standard and potentially curative therapy for hepatic colorectal metastases. However, up to two thirds of patients explored for resection are found to have unsuspected disease, which precludes resection. Methods: In order to determine if 18 F-FDG positron emission tomography (PET) scanning may prevent unnecessary surgery, a group of 40 patients being considered for hepatic resection but at high risk for unresectable disease by clinical criteria were subjected to whole body 18 F-FDG-PET scanning. Effect on clinical outcome was evaluated. In addition, PET findings in the 25 patients who underwent resection of hepatic metastases were directly compared with the resected specimen to determine the sensitivity of 18 F-FDG PET scanning in the liver. Results: Findings on 18 F-FDG-PET scanning influenced the clinical management in 16 patients (40%) and directly altered management in 9 cases (23%). Six patients were spared laparotomy, and 3 others had PET-directed surgery that found extrahepatic tumor and spared the patient unwarranted liver resection. In 3 cases PET missed peritoneal metastases found on laparotomy. In these cases all missed tumors were less than 1 cm in size. Out of 52 resected hepatic lesions, 18 F-FDG-PET detected 37. Within the liver, sensitivity of detection was also related to size. Only 25% of hepatic lesions smaller than 1 cm were detected by PET, while 85% of lesions larger than 1 cm were detected. Conclusions: FDG-PET is best for detecting extrahepatic disease. There are few false positives, and surgeons should carefully evaluate and biopsy extrahepatic positive sites. This test should be used for patients at high risk for extrahepatic disease and should be evaluated prospectively for all patients under consideration for liver resection.

Metabolic imaging with positron emission tomography (PET) for the staging and monitoring of treatment response has important implications in clinical oncology. The choice of radiotracer is likely to be critically important. The objective of our study was to compare the pharmacokinetics of C-11-methionine with FDG in a group of androgen independent patients with metastatic prostate cancer, to determine the differential metabolism of the two tracers, and to determine the optimal time of imaging after injection in treated and untreated patients. A total of 29 dynamic scans (19 pretreatment and 10 posttreatment) were performed in 10 patients with progressive or new lesions on bone scans (index lesions). A total of 13 index lesions were identified in baseline scans. Patients were infused with 370 MBq C-11-methionine on the couch and 32 dynamic images acquired over 60 minutes. After at least 5 half-lives of C-11, patients were then dynamically imaged (15 frames) for 45 minutes with FDG. Index lesions demonstrated both C-11-methionine (13/13) and FDG uptake (12/13). The plateau of methionine uptake in tumor was reached by 10 minutes, and thereafter remained constant. FDG tumor uptake was slower and for some patients continued to rise beyond 45 minutes. The clearance of blood activity for C-11-methionine was more rapid than FDG and the plateau was 10 and 45 minutes respectively. In 5 patients scanned after therapy, 4 responded to treatment, which was reflected by a corresponding decrease in C-11-methionine and FDG tumor uptake. No change was observed in the relative shape of the uptake curves however, between the C-11-methionine and the FDG uptake, either in the 4 who responded to treatment or for one patient who did not respond. The SUV of C-11-methionine was significantly higher than for FDG (P

In our clinical investigations focussing on improved therapeutic treatment of specific tumors we have concentrated on a targeted therapy approach utilizing designed radiolabeled monoclonal antibodies as the cytotoxic reagent. The physical characteristics of the alpha particle emitting radionuclide bismuth-213 including the short half-life of 45.6 min, has shown promise for the treatment of specific cancers such as leukemias and lymphomas or micrometastatic carcinomas. In an effort to increase the cytocidal effect of the HuM195, a humanized monoclonal antibody carrier to the CD33 antigen expressed on leukemia cells, our focus is directed toward an “internal” nano-generator composed of Ac-225 radionuclide, the parent of the bismuth-213. The actinium-225 radionuclide decays through several short-lived, alpha emitting daughters including francium-221, astatine-217 and bismuth-213. In order to study the biodistribution and the pharmacokinetics of the individual daughter nuclide, francium-221, the cyclotron production and separation of cesium radionuclides, specifically cesium-132, from a natural xenon gas target was undertaken. The choice of cesium as an analogue for francium was predicated upon both elements being in Group 1A alkali metals and cesium radionuclide possesses a sufficient half-life to allow biodistribution studies to be performed. The preliminary experimental results of this investigation are presented.

Sixteen patients with colorectal carcinoma and a rising serum carcinoembryonic antigen (CEA) level and no evidence of extra-abdominal disease were administered 5 mg of an anti-CEA monoclonal antibody (mAb), C110, labeled with approx. 5 mCi of 111In. All patients subsequently underwent exploratory laparotomy, and samples of tumor and normal tissue were obtained. Hepatic lesions (confirmed by histopathology) were visualized as areas of increased radiotracer uptake in 13 of 16 patients. Single photon emission computed tomography (SPECT) considerably aided detection, being positive in two patients with normal planar images. Ten of the 16 patients had positive x-ray computed tomographic (CT) images. The radioimmunodiagnostic study was falsely negative in 3 of 16 patients with subsequently proven hepatic disease, in one of whom CT was also normal. The antibody study was positive in 80% of lesions, thus being, in this small series, significantly more sensitive (P less than 0.01) than CT. 111In-C110 is a promising monoclonal antibody for the detection of hepatic metastases from colorectal carcinoma; this is the first study to show consistently greater concentration of 111In-labeled antibody in hepatic lesions than in surrounding normal hepatic parenchyma.

The synthesis of C5 labeled (±)-5-[11C]methyl-10, 11-dihydro-5H-dibenzo[a,d]cyclo-hepten-5, 10-imine [(±)-[11C]MK801] has been accomplished via alkylation of (±)-10, 11-dihydro-5H-dibenzo[a,d]cyclohepten-5, 10-imine-N-t-butylformamidine [(±)-5-des-methyl MK801 formamidine). The 11C labeling is accomplished by reaction of the anion of (±)-5-des-methyl MK801 formamidine, generated with s-butyllithium, and [11C]methyl iodide.

Nuclear medicine is the specialty of medical imaging which utilizes a variety of radionuclides incorporated into specific compounds for diagnostic imaging and therapeutic applications. During recent years research in this discipline has concentrated on the decay characteristics of particular radionuclides as well as upon the design of unique radiolabeled tracers necessary to achieve the time-dependent molecular image. Many of the radionuclides under consideration are accelerator produced. The cyclotron at Memorial Sloan-Kettering Cancer Center (MSKCC), one of the earliest accelerators dedicated to serve a medical research program, has undergone an extensive reconditioning effort to meet the challenges of enhanced operational performance and improved radiochemical production necessitated by the Center's clinical research effort. Special emphasis has been applied to the development of target systems in order to achieve pilot production of sufficient quantities of required radionuclides to undertake clinical evaluation of promising tracers.

The staff of the cyclotron facility at Memorial Sloan-Kettering Cancer Center is involved in a comprehensive radionuclide preparation program which culminates with the formulation of numerous requested short-lived, positron-emitting radiopharmaceutical agents for clinical investigation. Both the produced radionuclide as well as the final radiolabeled compound are subjected to stringent quality control standards including assays for radiochemical and chemical purity. The subtle chemical consequences resulting from the irradiation of a nickel-plated target for 13N production serve to emphasize some of these potential technical difficulties.

Objective. To develop a non-immunogenic human derived dual reporter gene system for simultaneous imaging of different molecular-genetic processes in humans using nuclear imaging techniques (PET) with potential suicide capabilities.

Objective. The studies of NK cell based therapies often have to address the question of the NK cells trafficking, homing, tumor targeting and therapeutic effect. We tested feasibility of applying a multi-modality imaging approach for assessment of therapeutic NK-92 cells trafficking and tumor targeting in mice model.

The excitation function for the production of 124 I and 123 I from deuterons on 124 Te has been measured over the energy interval of 7.5 to 23.6 MeV. The target used was a compressed tellurium powder target. The thick target yields for both radioisotopes have been calculated, radiochemical purity was determined and recovery of the isotopically enriched tellurium has been investigated.

Labeling of plasma transferrin with gallium was investigated to determine whether the gallium-transferrin complex could be effectively used as a macromolecular tracer in studies of capillary permeability using Positron Emission Tomography (PET). Three gallium-plasma preparations were tested and 2 h bio-distribution studies were performed in rats. The three preparations gave similar blood clearance and tissue distribution data, but the methods used for evaluating gallium-transferrin binding were found to be suboptimal. Gallium clearance from blood was biexponential with both components faster than that of 125I-albumin. Gallium distribution spaces in all tissues including intracerebral Walker-256 tumors were larger than those of albumin. These results indicate a relative instability of the gallium-transferrin complex in vivo, which appears to preclude its use as an acceptable radiolabeled protein for vascular permeability studies using PET.

The radiochemical synthesis of [ 18 F]Fluororaclopride (S-3,5-dichloro-6-methoxy- N -(1-(2-[ 18 F]fluoro-ethyl)-2-pyrrolidinylmethyl)salicylamide) is accomplished via a two step synthesis. [ 18 F]Fluoroethyltriflate is prepared by [ 18 F]fluoride displacement on the bis triflate of ethylene glycol. [ 18 F]Fluoroethyl triflate is then allowed to alkylate a secondary amine precursor to yield [ 18 F]fluororaclopride. Purification of the radiopharmaceutical involves use of a short silica BONDELUT column and subsequent reverse-phase HPLC. The final product is obtained with a radiochemical yield of approximately 15% (corrected for decay) in a synthesis time of approximately 50 min. Fluororaclopride displays a 3- to 4-fold lower affinity for the D 2 receptor than does raclopride.

The preparation of cyclotron-produced radionuclides for incorporation into clinically useful diagnostic agents requires special attention to quality control determinations. Of particular concern is the paucity of data on the toxicity of those chemical contaminants produced within the target during the bombardment and subsequent radiation cooling as well as those arising from materials used in the handling and construction of targets. At Mount Sinai Cyclotron Facility, a krypton-rubidium targetry system has been in use for five years. Consequently we shall use this targetry and generator system as an illustration of the problems created when such unexpected chemical moieties are encountered. The chemical species apparently formed by radiolytic processes as well as their effects on the chemical processing of the diagnostic agent are presented.

The mechanism of iodine for hydrogen and iodine for halogen exchange on chromatographic surfaces has been investigated by allowing no-carrier-added 131 I − to react with model aromatic compounds. Reactions with phenol and aniline resulted in 2- and 4-position substitution. The absolute yield and 2:4 ratio varied as a function of initial solvent used; hydrogen ion concentration; type of chromatographic surface; and contact time on the surface. Reaction with iodo- and bromophenols revealed that iodine for hydrogen exchange occurs more readily than iodine for halogen exchange. The results indicate that with aromatic systems the reactions occur by electrophillic substitution, the iodinating species arising from surface catalysed oxidation of 131 I − .

A new method of radioiodination, apparently involving halogen exchange by surface catalysis, has been developed for the synthesis of 131I-4-iodoantipyrine (131I-4-IAP) in high specific activity. On a silica gel surface, for instance, radioiodide reacts with antipyrine (AP) in hydrochloric acid at pH 1.0 to form 131I-4-IAP in a radiochemical yield of 82.2 ± 1.8%. Subsequent separation of the 131I-4-IAP from the AP by thin layer chromatography (TLC) has afforded greater than 99.5% radiochemically pure 131I-4-IAP. Quality control procedures utilizing TLC and high performance liquid chromatography have been developed.

Many of the uniquely labelled synthetic precursors currently employed in the design of sophisticated radiolabelled compounds have their origins in the field of hot atom chemistry. Particularly, the development during the past few years of automated, on-line synthetic procedures which combine the nuclear reaction, hot atom and classical chemistry, and rapid purification methods has allowed the incorporation of useful radionuclides into suitable compounds of chemical and biochemical interest. The application of isotopically labelled methyl iodide, formaldehyde, and cyanide anion as synthetic intermidiates in research involving human physiology and nuclear medicine, as well as their contributions to other scientific methodology, is reviewed.

Gas targets are utilized in the production of a variety of cyclotron produced radionuclides of value to clinical nuclear medicine. We report the design and construction of a novel cyclotron gas target which both facilitates the collection and the processing of the target gas as well as the desired rubidium-81 species. In addition, preliminary excitation curves are presented for some of the concurrently produced krypton isotopes. The reaction of protons whose energies were between 17.5 and 24 MeV on natural krypton gas were evaluated in hopes of ultimately preparing 85m Kr with moderate specific activity. The ratio of the yield of the radiorubidium species provided an intrinsic energy monitor for the determination of the average proton energy within the target.

1-[ 11 C]Butanol was synthesized via two routes: carbonylation of an organoborane and carbonation of a Grignard reagent. The reaction of 11 CO with B- n -propyl-9-borabicyclo[3.3.1]nonane, followed by oxidation in alkaline medium, produced 1-[ 11 C]butanol in 33–71% yield (EOB) in 60 min. The reaction of 11 CO 2 with 1-propylmagnesium bromide, followed by a lithium aluminum hydride reduction, produced 1-[ 11 C]butanol in 55–74% yield (EOB) in 25–27 min. The radiochemical purity was 95–99% in each case.

Carbon-11 labeled urea was synthetized by thermal transformation of 11 C-labeled ammonium cyanate. The 11 C-cyanate was prepared by oxidation of 11 C-cyanide. The total synthesis was accomplished in 20 min starting from 11 CN − to obtain 11 C-urea in 85±5% radiochemical yield with purity greater than 98%. HPLC was utilized to examine the various reactants and products.

[11C]Methane, produced from the (p, α) nuclear reaction on a nitrogen-5.6% hydrogen target, has been oxidized in an “on-line” synthetic train to yield [11C]carbon dioxide. [11C]methane is quantitatively adsorbed from the target gas on a Porapak Q column cooled to liquid nitrogen temperature. Following absorptive concentration, the [11C]methane is oxidized by passage over cobalt(II–III) oxide powder heated to 500°C in a stream of nitrogen-2.0% oxygen. The isotopic dilution occurring during this conversion was determined to be 60%.

Use of [ 11 C]urea as an intermediate for the preparation of “no-carrier-added” radiopharmaceuticals required optimization of synthetic parameters. A procedure has been developed to produce [ 11 C]urea from “no-carrier-added” 11 CN − within 16 ± 1 min from end of bombardment (EOB) with a radiochemical yield of 95.0 ± 2.5%.

[11C]carbon dioxide was prepared from [11C]cyanide. First, [11C]CH4 was produced by the (p, α) reaction on a N2/H2 mixture and was converted to [11C]CN− by reaction with ammonia over platinum at 1273 K. The [11C]CN− was adsorbed on a cobalt(II, III) oxide/ceramic furnace material at room temperature and was subsequently converted to [11C]CO2 by heating the cobalt(II, III) oxide to 948 K over a 10 min period and collecting the [11C]CO2 in a trap at 77 K. Specific activities as high as 600 mCi/μmol at end of bombardment (EOB) were obtained in a 15 μA irradiation for 10 min.