Brian M. Gallagher

18F-5-fluorouridine, A New Probe For Measuring The Proliferation Of Tissue in vivo☆

(1) Increased metabolic trapping of labeled fluorouridine reflects the interaction of three parameters in rapidly proliferating tissues: increased rates of intracellular phosphorylation, increased rates of transport, and increased rates of synthesis of RNA. (2) We have taken advantage of these metabolic phenomena, demonstrating in this paper that the uptake of 18F-5-fluorouridine, a positron-emitting radiopharmaceutical, can provide a very practical means for measuring changes in proliferative states of tissues in vivo. (3) Two major changes in proliferative states have been examined: one involves changes in growth of normal mouse tissues induced by pharmacological agents; the other involves tumor growth and neoplastic infiltration in mice and rabbits. (4) We describe tracer experiments with 18F-5-fluorouridylate, prepared by enzymatic means, and with 18F-5-fluorouridine, prepared by both enzymatic means and direct radiochemical procedures. (5) Uptakes of 18F after a pulse of 18F-5-fluorouridine were increased in mouse spleen following phenylhydrazine treatment to induce increased splenic erythropoiesis. (6) Uptakes of 18F in various mouse tissues were decreased following pretreatment with actinomycin D. This finding is consistent with the known inhibitory action of actinomycin on RNA synthesis. (7) Intracerebral Zimmerman ependymoblastoma tumors showed extraordinarily high uptakes of fluorine-18 in mice injected intravenously with 18F-5-fluorouridylate or with 18F-5-fluorouridine in contrast to very low uptakes by normal brain tissue. (8) After intracerebral injection of mice with suspensions of L1210 leukemia cells, distant organs such as lung, liver, and spleen became involved. These tissues showed significant increases of radioactivity after pulse labeling with 18F-5-fluorouridylate consistent with histological evidence for infiltration of these tissues by neoplastic cells. (9) Intramuscular VX2 carcinoma tumors in rabbits showed localized uptakes of 18F significantly higher than surrounding normal muscle tissue. (10) The most important clinical implication of the present work is the promise that 18F-5-fluorouridine uptakes can be followed in humans by positron emission tomography. This would provide a direct means of measuring different rates of in vivo proliferation in neoplasms, hematologic tissues and other organs undergoing rapid growth changes.

Cyclotron isotopes and radiopharmaceuticals--XXVIII. Production of potassium-38 for myocardial perfusion studies.

Abstract The 40 Ar( p ,3 n ) 38 K nuclear reaction was developed into a routine method for the cyclotron production of 38 K for dynamic studies in conjunction with computed positron emission transaxial tomography. The 7.62-min half-life of 38 K is theoretically and experimentally ideal for obtaining quantitative regional myocardial perfusion data and tomographic images of the canine myocardium. Potassium-38 may be of considerable clinical utility at institutions with on-site accelerators.

Evaluation of radiorespirometry for the determination of monoamine oxidase activity in vivo utilizing [11c]octylamine as a substrate

Abstract The inhibition of MAO in vivo by pargyline in mice has been studied to evaluate the usefulness of n -octylamine · HC1[1- 1 1C], a substrate of MAO that is rapidly metabolized to 11 CO 2 , as a probe of MAO activity in vivo . In pargyline-pretreated mice, the rate of decline in tissue levels of [ 11 C] n -octylamine after intravenous administration was decreased to an extent that varied with the particular tissue and the time after pargyline pretreatment. Likewise, pargyline-treated mice showed a reduced excretion of 11 CO 2 after [ 11 C] n -octylainine administration but not after octanoie acid[1- 11 C] or octanol[1- 11 C] injection. The duration of inhibition of 11 CO 2 excretion after pargyline treatment paralleled reasonably well the inhibition of MAO measured directly in intestine and liver, but the inhibition of MAO in the lung, kidney and brain persisted longer. Direct measurement of mitochondrial MAO activity using [ 14 C]octylamine showed the following: intestine > liver > lung > brain 》 kidney. At 94 hr after pargyline administration, 11 CO 2 excretion was close to the control value yet the MAO activity of brain, lung and kidney was less than half of the control value. Thus, the rate-determining step in the overall rate of 11 CO 2 excretion appears not to be the MAO-catalyzed step but the reactions occurring after deamination.

Cyclotron isotopes and radiopharmaceuticals—XXIX. 81, 82mRb for positron emission tomography☆☆☆

Abstract Cationic 81, 82 m Rb was produced via ( p, xn ) reactions with E p = 32 → 16 MeV on Kr in >99.95% radionuclidic purity at a EOB + 3 h combined production rate of 17.3 mCi/μAh. The 81, 82 m Rb was evaluated in dogs as a myocardial perfusion agent in combination with quantitative positron emission transaxial tomography, and with a planar positron camera for focal plane tomography. The 81, 82 m Rb radionuclides are promising substitutes for 38 K + at institutions which do not have an on-site accelerator.

Multiple monoamine oxidase activities in heterogeneous populations of mouse lung mitochondria

Abstract Both monoamine oxidase (MAO) A and B activities were almost exclusively found associated with mitochondrial fractions in mouse lung, and these activities could be partially separated on linear sucrose gradients. The peak MAO B activity measured by the deamination of β-phenylethylamine (PEA) was consistently found in a population of mitochondria sedimenting in a denser region of the gradient than peak MAO A activity for 5-hydroxytryptamine (5-HT). Clorgyline strongly inhibited deamination of 5-HT across the mitochondrial fractions, while deamination of PEA remained high. Pargyline blocked PEA deamination, while considerable activity remained for 5-HT. These results provide evidence for the possible existence of heterogenous subpopulations of lung mitochondria differing in sedimentation behavior and containing monoamine oxidase with different substrate specificity and inhibitor sensitivity.

METABOLIC TRAPPING AS A PRINCIPLE OF RADIO-PHARMACEUTICAL DESIGN: SOME FACTORS RESPONSIBLE FOR THE BIODISTRIBUTION OF 18F-2-DEOXY-2-FLUORO-D-GLUCOSE

Initially, [18F]2-deoxy-2-fluoro-D-glucose (F-18-DG) distributes to the kid neys, heart, brain, lungs, and liver of the mouse, and clears rapidly from all except the heart and, to a much lesser extent, the brain. The heart and brain showed the highest rates of phosphorylation both in vivo and in vitro. No detectable glucose-6-phosphatase activity was present in these organs when hexokinase activity was high and at pH 6.5. The rank order for hexokinase activity, measured in vitro, was brain > heart •kidney > lung > liver, whereas glucose-6-phosphatase activity was found only in the liver and to a lesser extent in the kidney, at pH 6.5. The rate of appearance of F-18-DC-6 phosphate (F-18-DG-6-P) in vivo was significantly slower in the lungs, liver, and kidneys than in the heart and brain, and represented a small proportion of the initial radioactivity. The F-18-DG that clears from the organs is excreted into the urine mostly unchanged, apparently due to the lack of tubular resorption. The rapid excretion of F-18-DG from liver, lungs and kidneys, and the retention by the heart and brain, is the result of metabolic trapping within certain organs and is reflective of glucose utilization. These results may contribute to the clinical utility of F-18-DG by providing a basis Ior metabolicstudiesin vivo. Metabolic trappingcan be consideredas a principle in the design of radiopharmaceuticals as metabolic probes for

Tissue distributions of radiopharmaceuticals labeled with positron emitters and problems in relating them to human studies

This paper discusses a few specific examples of organ distributions involving positron-emitting nuclides intended to illustrate some specific points in this area. In particular, work with 2-fluoro-2-deoxyglucose will be discussed in some detail, and its distribution in the body compared with the closely related (chemically but not biologically) 3-fluoro-3-deoxyglucose and 1-/sup 11/C-2-deoxyglucose. Other compounds labeled with these two nuclides, and with /sup 13/N and /sup 15/O will also be discussed.

125I-β-iodo-D-alanine-synthesis, biodistribution and antimicrobial activity

Methyl N-carbobenzoxy-β-iodo-D-alaninate (1) served as an intermediate to synthesize methyl β-iodo-D-alaninate (2) and β-iodo-D-alanine (3). The 125I-labeled compound 1 was synthesized by the melt method and used to synthesize 125I-labeled compounds 2 and 3. Compound 3 was shown to be substrate for D-amino acid oxidase. It was also shown that compounds 2 and 3 were rapidly eliminated from normal mammalian tissues and that compound 3 inhibited the Escherichia coli growth in a dose-dependent manner at 100–500 μg/ml while compound 2 showed no effect at 500 μg/ml level. Therefore, it was suggested that compound 3 may serve as an abscess localizing agent.