Radiosynthesis of [18F] N-3-fluoropropyl-2-beta-carbomethoxy-3-beta-(4-iodophenyl) nortropane and the first human study with positron emission tomography.

A procedure for the routine preparation of [18F]FP-CIT has been developed. Purification of the final product was achieved by preparative HPLC using phenethyl column without decomposition or epimerization. [18F] labeled-N-fluoropropyl-2 beta-carbomethoxy-3 beta-(4-iodophenyl) nortropane was prepared and PET imaging was performed on human subjects. A high uptake into striatal regions was observed. HPLC plasma analysis using [18F]FP-CIT indicated the presence of only one metabolite. By directly comparing the behavior of these three radiotracers ([18F]DOPA, [123I]FP-CIT, and [18F]FP-CIT) in the same subjects, we can enhance our understanding of the dopaminergic system as well as the relative potential of these techniques in a clinical research setting.

Clinical significance of striatal DOPA decarboxylase activity in Parkinson's disease.

UNLABELLED: We performed dynamic PET studies with fluorodopa (FDOPA) in 9 normal volunteers and 16 patients with Parkinson's disease to investigate the applicability of dopa decarboxylase (DDC) activity measurements as useful markers of the parkinsonian disease process. METHODS: From the 3-O-methyl-FDOPA (3OMFD)/PET studies, we obtained mean population values of the kinetic rate constants for 3OMFD (K1M = 0.0400 and k2M = 0.0420). We applied these values to calculate striatal DDC activity using the FDOPA compartmental model. We estimated k3D in this group using dynamic FDOPA-PET and population mean K1M and k2M values. We then applied the mean population K1M and k2M values to estimate k3D(pop) to a new group (6 normal volunteers and 11 patients) studied only with dynamic FDOPA-PET. In all FDOPA/PET studies, we calculated striatal uptake rate constants (KiFD) using a graphical method and also measured the striato-occipital ratio (SOR). RESULTS: Although DDC activity has been postulated as a precise indicator of presynaptic nigrostriatal dopaminergic function, KiFD and SOR provided better between-group discrimination than did estimates of striatal DDC activity. KiFD and k3D(pop) both correlated significantly with quantitative disease severity ratings, with a similar degree of accuracy (r = 0.69 and 0.63 for k3D(pop) and KiFD, respectively; p < 0.01). CONCLUSION: Although estimated striatal DDC activity correlates with clinical disability, this measure is comparably less effective for early diagnosis. We conclude that a simple estimate such as striatal KiFD is superior to k3D measurements for most clinical and research applications.

Assessment of disease severity in parkinsonism with fluorine-18-fluorodeoxyglucose and PET.

UNLABELLED: Fluorine-18-fluorodeoxyglucose (FDG) and PET have been used to identify an abnormal regional metabolic covariance pattern in Parkinson's disease (PD). To examine the potential use of this covariance pattern as a metabolic imaging marker for PD, we describe the Topographic Profile Rating (TPR), which is a method for calculating subject scores for this pattern in individual PD patients. We then assess the relationship between these metabolic measures and objective independent disease severity ratings. METHODS: Two independent groups of PD patients were studied with FDG-PET. Group A consisted of 23 patients (mean age 60.2 +/- 12.2; mean Hoehn and Yahr stages 2.4 +/- 1.3) and Group B had 14 patients (mean age 49.0 +/- 12.1; mean Hoehn and Yahr stage 3.2 +/- 1.2). The regional cerebral metabolic rates for glucose (rCMRGlc) in all patients in each group were measured. TPR was used to calculate subject scores for the disease-related covariance pattern on a patient-by-patient basis. RESULTS: In both PD patient groups, subject scores correlated with Hoehn and Yahr disease severity ratings (Group A: r = 0.59, p < 0.004; Group B: 0.57, p < 0.04), quantitative ratings for bradykinesia (Group A: r = 0.63, p < 0.002; Group B: r = 0.61, p < 0.03), rigidity (Group A: r = 0.59, p < 0.004; Group B: r = 0.59, p < 0.04), but not with tremor. CONCLUSION: These findings indicate that regional metabolic covariance patterns are robust imaging markers of disease severity. FDG-PET may be useful clinically in assessing parkinsonian disability and disease progression.

Striatal hypometabolism distinguishes striatonigral degeneration from Parkinson's disease.

Regional and global metabolic rates for glucose were estimated using 18F-fluorodeoxyglucose and positron emission tomography in 10 patients with a clinical likelihood of striatonigral degeneration (2 men and 8 women; mean age, 61.8 +/- 6.9 years; mean disease duration, 4.7 +/- 2.2 years; mean Hoehn and Yahr score, 3.5 +/- 0.8). Measures of brain glucose metabolism in these patients were compared with those for 10 age-matched normal volunteers, 10 disease severity-matched patients with Parkinson's disease (PD), and 10 disease duration-matched patients with PD. Normalized glucose metabolism was significantly reduced in the caudate (p < 0.03) and putamen (p < 0.003) as compared with that in normal and PD control subjects, and discriminated patients with striatonigral degeneration from control subjects (p < 0.002). Putamenal hypometabolism in patients with striatonigral degeneration correlated significantly with quantitative ratings of motor disability (p < 0.02). These results suggest that quantitative 18F-fluorodeoxyglucose positron emission tomography techniques may be useful in supporting a diagnosis of striatonigral degeneration in life, and in objectively assessing disease severity and potential therapeutic interventions.

Comparative bioavailability characteristics of commercial quinidine polygalacturonate and sulfate tablets.

This study compared the relative bioavailability characteristics of quinidine polygalacturonate (QP) and quinidine sulfate (QS) after oral administration of commercial tablets and a liquid form prepared from crushed tablets in 13 healthy adult male volunteers. Each subject received the following four single-dose treatments in a randomized, crossover manner with a one-week washout period between treatments: 400 mg QS liquid, two 200-mg QS tablets, 550 mg QP liquid, and two 275-mg QP tablets. All four treatments were equivalent in terms of the dose of quinidine base. Multiple serum samples and two 24-hour urine specimens were collected over 24 and 48 hours, respectively, and assayed for quinidine with a specific HPLC assay method. For the absorption and disposition parameters measured (maximum serum concentration, time to reach maximum concentration, area under the concentration-time curve [0-48 hours], absorption and elimination rate constants, absorption and elimination half-lives, apparent total body clearance, apparent volume of distribution, and dose fraction excreted in the urine) no significant differences were observed for any of the parameters among the four treatments (p greater than 0.05). The results of the present investigation demonstrated that QP and QS produced identical serum quinidine concentration-time curves when given in the form of a tablet or liquid. The clinical implications of these observations with respect to the dosing of QP are discussed.

Xenon-127m: a new radionuclide for applications in nuclear medicine.

Xenon-127m (127mXe) emits two gamma rays in cascade, with half-life of 69.2 +/- 0.9 sec. The first has the energy of 172.5 keV, and is emitted from the nucleus in 38% of the decays. The second gamma ray has the energy of 124.8 keV and is emitted from the nucleus in 69% of the disintegrations. Together they furnish 107 easily collimated gamma rays per 100 decays. Xenon-127m is generated readily by bombarding nearly saturated aqueous solutions of sodium or potassium iodide with 14-MeV protons. The 127mXe is swept out continuously, as it is produced, by bubbling helium upward through the solutions. Up to approximately 100 mci/l are obtained from the resulting mixture of gases. The 127mXe + helium is admixed with about five volumes of air (or oxygen) and then driven continuously to a scintillation camera located approximately 200 yd distant. When the mixture of gases is inhaled, high quality images of the lungs are obtained by means of an Anger scintillation camera.

Thin layer chromatographic detection of kryptofix 2.2.2 in the routine synthesis of [18F]2-fluoro-2-deoxy-D-glucose.

A simple procedure for the detection of 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo (8.8.8) hexacosane (Kryptofix 2.2.2) in the final solution of [18F]FDG prepared by the aminopolyether supported nucleophilic substitution of 1,3,4,6-tetra-O-acetyl 2-O-trifluoromethanesulfonyl-beta-D-mannopyranose (Hamacher et al., 1986) has been developed. Presence of Kryptofix 2.2.2 in the routine production of [18F]FDG was detected using methanol/ammonium hydroxide (9:1) solvent system. A method to remove Kryptofix from [18F]FDG solution has been suggested.

Imaging studies of patients with malignant fibrous histiocytoma using C-11-alpha-aminoisobutyric acid (AIB).

Alpha-aminoisobutyric acid (AIB), a synthetic, nonmetabolized amino acid which is rapidly transported into viable cells by the A-type or alanine-preferring amino acid transport system, has been labeled with the short-lived, positron-emitting radionuclide carbon-11. Carbon-11 labeled AIB is currently being evaluated as a tumor imaging agent for in vivo amino acid transport studies in patients with cancer. In this study, C-11 AIB was used to image two patients with malignant fibrous histiocytoma (MFH), a pleomorphic sarcoma. Following intravenous administration of C-11 AIB, tumors in the distal femur of one patient and in the anterior chest wall of another patient were well visualized using high energy gamma scintigraphy. Since therapy may alter the accumulation of amino acids in tumor tissue, studies using C-11 AIB in patients with MFH before and after chemotherapy are in progress.

Krypton-79m: a new radionuclide for applications in nuclear medicine.

Krypton-79m emits 130-keV gamma rays in 27 +/- 1% of its disintegrations and decays with a half-life of 50 +/- 3 sec. It is generated readily by bombarding nearly saturated aqueous solutions of bromide salts, or bromoform, with 14-MeV protons. The 79mKr is swept out continuously as it is produced by bubbling helium upward through the liquids. Up to 200 mCi per I are obtained of the resulting mixture of gases. The 79mKr + helium is mixed with about five volumes of air and then driven continuously through a small-bore tube to an Anger scintillation camera located approximately 200 yards away. The rate of flow is adjusted so that the amounts of 13-sec 81mKr and of 35-hr 79Kr are inconsequential at the time and point of use. When the gases are inhaled, good images of the lungs are obtained with an Anger scintillation camera. The trachea and bronchi commonly are revealed also.

Evaluation of [1-11C]-alpha-aminoisobutyric acid for tumor detection and amino acid transport measurement: spontaneous canine tumor studies.

Alpha-aminoisobutyric acid (AIB), or alpha-methyl alanine, is a nonmetabolized amino acid transported into cells, particularly malignant cells, predominantly by the 'A' amino acid transport system. Since it is not metabolized, [1-11C]-AIB can be used to quantify A-type amino acid transport into cells using a relatively simple compartmental model and quantitative imaging procedures (e.g. positron tomography). The tissue distribution of [1-11C]-AIB was determined in six dogs bearing spontaneous tumors, including lymphosarcoma, osteogenic sarcoma, mammary carcinoma, and adenocarcinoma. Quantitative imaging with tissue radioassay confirmation at necropsy showed poor to excellent tumor localization. However, in all cases the concentrations achieved appear adequate for amino acid transport measurement at known tumor locations. The observed low normal brain (due to blood-brain barrier exclusion) and high (relative to brain) tumor concentrations of [1-11C]-AIB suggest that this agent may prove effective for the early detection of human brain tumors.

Selective alkylation of pyrimidyldianions: synthesis and purification of 11C labeled thymidine for tumor visualization using positron emission tomography.

Reaction of 5-bromo-2'-deoxyuridine and dihydropyran in THF gave a tetrahydropyranyl ether derivative which, after treatment with n-butyllithium, was selectively alkylated in situ by [11C]methyl iodide to give [methyl-11C]thymidine and unlabeled 2'-deoxyuridine. The labeled compound can be isolated by HPLC on a reversed phase column in 12 min. The ether derivative is stable which makes it possible to prepare 11C labeled thymidine by organic synthesis in 17-25% radiochemical yield in 30-45 min with radiopurities greater than 99%. In a synthesis with no-carrier-added, a radiochemical yield of 20% was obtained. Carrier added syntheses gave 2.4-4.7 mCi of [11C]thymidine with specific activities of 250-300 mCi/mmol.

Synthesis and quality assurance of [11C]alpha-aminoisobutyric acid (AIB), a potential radiotracer for imaging and amino acid transport studies in normal and malignant tissues.

Carbon-11 labeled alpha-aminoisobutyric acid (AIB), a synthetic amino acid, was prepared by the modified Bucherer-Strecker amino acid synthesis from acetone, ammonium carbonate and [11C]KCN in the presence of carrier KCN. This method results in the labeling of AIB in the carboxyl group. The label is stable in this position because AIB is not a metabolized after cellular uptake. AIB is rapidly accumulated in viable cells including malignant cells. Since it is a non-metabolized amino acid, AIB offers the possibility of studying amino acid transport in vivo without interference by radiolabeled metabolic products. Radiochemical yields of [11C]AIB of 35-60% have been obtained in 70-80 min with radiopurities greater than 99%. Carrier added syntheses gave 15-25 mCi of [11C]AIB with specific activities of 0.3 Ci/mmol. Our quality control program which insures that [11C]AIB is suitable for imaging studies in patients with cancer includes HPLC analyses of product identity and purity, apyrogenecity and isotonicity assays, and a sensitive test for cyanide.

Design for a multiple target system for a medical cyclotron.

A novel target system has been designed for a compact cyclotron. The system permits one of three or more targets to be selected remotely for bombardment, permits all target and chemical operations to be controlled remotely, causes no change in beam energy or beam current, occupies a limited space, and is simple to construct and maintain. The targets are mounted to a flexible bellows-multiple port manifold assembly, supported on a fan-shaped turntable. A motor moves the system to align the target to be bombarded with the main beam axis. Designs for two subassemblies are also presented. These are a retractable target chamber for water and a remotely controlled variable collimator.

Synthesis and body distribution of alpha-aminoisobutyric acid-L-11C in normal and prostate cancer-bearing rat after chemotherapy.

This paper describes the synthesis of alpha-aminoisobutyric acid-11C (11C-AIB) and studies its body distribution in healthy and tumor-bearing animals. High tissue levels of 11C-AIB were found in organs with high metabolic activity (pancreas, liver, kidney). The prostate tumor 11C-AIB concentrations are significantly lower than that of pancreas, liver, and kidney, but increased when compared with normal prostate levels. Effective chemotherapy, which reduces tumor growth of two different prostate adenocarcinoma cell lines (R-3327-H, R-3327-G) also decreases 11C-AIB levels and the 11C-AIB prostate to tumor ratio.

Production of 7.6-minute potassium-38 for medical use.

A method is described for generating 20--30 mCi of 7.6-min potassium-38 by means of a small cyclotron. Sodium chloride is mounted on a water-cooled tantalum plate, by evaporation from an aqueous solution. It is bombarded with 14.7 MeV helium-4 ions, at 50 microA. The K-38 is produced free of other radionuclides. For intravenous injection the bombarded NaCl is dissolved in sufficient pyrogen-free water to make an isotonic saline solution, which then is sterilized by filtration. Other methods of production investigated were the bombardment of: carbon tetrachloride with He-4 ions; calcium oxide with 7.8-MeV deuterons; and potassium chloride with 23-MeV He-3 ions. These gave products that were unsuitable for clinical applications. Chiefly because of the short half-life of K-38, the whole-body radiation exposure is estimated to be only about 12 mrad/mCi, and exposures to the heart and kidneys are approximately ten times greater.