Joseph M. McDonald

The dynamics of ammonia metabolism in man. Effects of liver disease and hyperammonemia.

The cyclotron-produced radionuclide, 13N, was used to label ammonia and to study its metabolism in a group of 5 normal subjects and 17 patients with liver disease, including 5 with portacaval shunts and 11 with encephalopathy. Arterial ammonia levels were 52-264 micron. The rate of ammonia clearance from the vascular compartment (metabolism) was a linear function of its arterial concentration: mumol/min = 4.71 [NH3]a + 3.76, r = +0.85, P less than 0.005. Quantitative body scans showed that 7.4 +/- 0.3% of the isotope was metabolized by the brain. The brain ammonia utilization rate, calculated from brain and blood activities, was a function of the arterial ammonia concentration: mumol/min per whole brain = 0.375 [NH3]a - 3.6, r = +0.93, P less than 0.005. Assuming that cerebral blood flow and brain weights were normal, 47 +/- 3% of the ammonia was extracted from arterial blood during a single pass through the normal brains. Ammonia uptake was greatest in gray matter. The ammonia utilization reaction(s) appears to take place in a compartment, perhaps in astrocytes, that includes less than 20% of all brain ammonia. In the 11 nonencephalopathic subjects the [NH3]a was 100 +/- 8 micron and the brain ammonia utilization rate was 32 +/- 3 mumol/min per whole brain; in the 11 encephalopathic subjects these were respectively elevated to 149 +/- 18 micron (P less than 0.01), and 53 +/- 7 mumol/min per whole brain (P less than 0.01). In normal subjects, approximately equal to 50% of the arterial ammonia was metabolized by skeletal muscle. In patients with portal-systemic shunting, muscle may become the most important organ for ammonia detoxification. Muscle atrophy may thereby contribute to the development of hyperammonemic encephalopathy with an associated increase in the brain ammonia utilization rate.

Enzymatic Synthesis and Organ Distribution Studies with 13N-Labeled L-Glutamine and L-Glutamic Acid1

A method was developed for producing several hundred mCi of 13NH3 with subsequent enzymatic synthesis of large amounts of 13N-labeled glutamine and glutamic acid. Dynamic measurements and quantitative whole body scans demonstrated greater glutamine uptake in the liver region of mongrel dogs than uptake of glutamic acid or NH3, although all concentrated in the liver to a significant degree. Myocardial uptake of glutamine and glutamic acid was low, while NH3 was incorporated into the heart, brain, bladder, and kidneys at a greater rate than the amino acids.

Imaging of tumors involving bone with 13N-glutamic acid.

Nitrogen-13 labeled L-glutamic acid was evaluated as an imaging agent for tumors involving bone. The enzymatically prepared labeled compound was administered intravenously to dogs with spontaneous tumors, and tumor uptake was determined with a gamma camera and rectilinear scanner. These tumors were well visualized with 13N-glutamic acid, and the results compared favorably with uptake studies performed on the same animals with 99mTc-diphosphonate.

Distribution of oxygen-15 in the dog at the steady-state.

Abstract Severe limitations imposed by rapid decay have not permitted conventional imaging techniques to be applied using the radioactive isotopes of oxygen. This has been overcome by the application of a steady-state procedure in which the agent is delivered to and utilized by the subject at a constant rate. Air, containing 15O2, was administered continuously by inhalation to a normal dog. Levels of activity were monitored over several body regions using external probes. At the steady-state, either regional or whole body imaging was performed. High levels of activity permitted well defined images of the brain, heart, lungs, liver, kidney and testes.

Regional Imaging with Oxygen-14

The metabolic significance of the distribution of labeled oxygen was studied in the dog by inhalation of gas mixtures labeled with oxygen-14 (T1/2 = 71 seconds) maintained at a constant level of activity. Under steady-state conditions, whole body images were developed by detection of the positron annihilation emissions with a dual head rectilinear scanner in the coincidence mode.

A Compact in-House Multi-Particle Cyclotron for Production of Radionuclides and Labeled Compounds for Medical Use

The Sloan-Kettering cyclotron located with covered access to two large hospitals, Memorial Hospital for Cancer and the New York Hospital, can accelerate deuterons to 8 MeV, protons and He-4 ions to 15 MeV and He-3 iohs to 23 MeV. A large number of radionuclides can be produced with these four particles and many compounds of physiological significance may be labeled. Methods will be described for the production of 15O as O2, CO and CO2 11C as CO, CO2, HCN, and other precursors for organic synthesis; 13N as N2, NO3-, NH4+ and 13N-labeled L-amino acids; 18F as NaF; 52Fe as ferrous citrate; 38K as KC1. Yields will be discussed, as well as the uses to which these radio indicators are put. The use of radioisotopes carbon-11, nitrogen-13 and fluorine-18 enables one to label compounds of true physiological or biochemical significance, and the concurrent development of instrumentation to quantitatively detect the localization of such compounds in the human body offers the opportunity to study phenomena heretofore impossible in the intact human, in a safe, non-invasive way. Examples of compounds which can be studied in this way are hormones, e.g. estradiol, for detection of breast cancer, amino acids for the detection of protein synthesis in tumors and the pancreas, precursors of DNA and RNA for the detection of abnormal cell growth, drugs related to neural disorders, e.g. haloperidol in schizophrenia.