Hot Atom Chemistry 1968-1976
Hot atom chemistry was "invented" during the burgeoning of science following World War II. By the late sixties, the AEC funded groups in the National Laboratories and in universities with access to cyclotrons, that used the technique as a means of studying detailed chemical reaction mechanisms with isotopes of H, Cl, F, C, Tl, and other atoms, although most of the work involved organic molecules. Then a revolution occurred. The synthetic methods used to incorporate and analyze isotopically labeled atoms into molecules, and the techniques used to follow the reactions of the radioactive species were ideally suited for the new field of nuclear medicine. By the end of this period, "traditional" hot atom chemistry was rapidly disappearing, its place taken by sophisticated molecular beam methods, and certain practitioners of hot atom chemistry were adopted into the medical imaging community.
Traditional Hot Atom Chemistry: Studies of carbon-11 stripping and abstraction reaction mechanisms: Carbon-11 is an radioactive isotope used in labeling compounds for medical research (see below). In order to prepare labeled compounds for this purpose, it is important to understand the reaction mechanisms by which 11C is incorporated. Energetic 11C atoms were produced by irradiating known-composition mixtures of perprotonated and perdeuterated alkane-O2 mixtures with 33 Mev protons from the BNL 60-inch Cyclotron, generating 11C atoms by the 12C(p,pn)11C reaction. The relative yields of 11C2HD, 11C2H2,and 11C2D2 products were used as indicators of inter- vs. intramolecular formation mechanisms (R.M. Lambrecht, N. Furukawa and A.P. Wolf, J. Phys. Chem. 74 4605 (1970).
Stereospecific Chlorine Replacement in Substituted Cyclopropanes. An investigation of chlorine hot-atom replacement at an asymmetric center was carried out in order to check the observation by other workers that front-side attack of the hot atom was the major mode of replacement. These studies involved a molecule with only one asymmetric center, 1-chloro-2,3-dimethylcyclopropane. The syn, anti, and trans forms of this molecule were prepared and irradiated. The results show that the displacement reaction is > 95% stereospecific in the gas phase, with ease of substitution being greater in the anti isomer. Experiments involving dilution of the isomer, so that the 38Cl atom must react with the substrate rather than another chlorodimethylcyclopropane molecule, show that lack of bond rupture cannot be a valid explanation for the observed stereospecificity. These experiments show further that displacement of chlorine by a hot 38Cl atom is from the front side (i.e., inversion does not occur), that the atom must be undergoing the reaction at energies near thermal since there is a clear steric hindrance effect, and that the lack of bond rupture is insignificant in the 37Cl(n,g)38Cl reaction in an organic molecule.
Application of Hot Atom Reaction Studies in Medicine: One of the most significant developments in medicine during the twentieth century was the pioneering work of Dr. George T. Cotzias in the Brookhaven Medical Department introducing the use of L-dopamine for the treatment of Parkinson's disease. Preparation of 11C-labeled dopamine was necessary for mechanistic studies of this compound's efficacy. Labeled dopamine was prepared by a combination of nuclear recoil and organic synthesis. The technique developed involved hot atom preparation of cyanide followed by incorporation of the cyanide into an organic precursor of dopamine. Chemical methods were then used to lead to 11C dopamine. The entire procedure could be completed in one hour. Direct recoil labeling of L-dopamine, tryptophan, and other amino acids was also performed. In these syntheses, chemically pure materials were obtained in thirty minutes or less after proton irradiation, a necessary feature if radiopharmaceuticals were to be useful for medical and research purposes (J.S. Fowler, A.N. Ansari, H.L. Atkins, P.R. Bradley-Moore, R.R. MacGregor and A.P. Wolf, J. Nucl. Med. 14 867 (1973).
Finally, while first published in 1977, slightly outside the period described herein, much of the work leading to the synthesis of 18F-labeled 2-deoxy-2-fluoro-D-glucose, (FDG) was performed during this time, so it is included here. Positron Emission Tomography has completely revolutionized the study of brain function. Using this technique, researchers can observe and correlate, in details, the structure, chemical activity, and response of the brain at work. The widely used molecule that permitted this revolution was 18F-labeled 2-deoxy-2-fluoro-D-glucose, developed collaboratively by researchers at Brookhaven, the University of Pennsylvania, and the National Institutes of Health. References to the primary literature include the following:
B.M. Gallagher, A. Ansari, H. Atkins, V. Casella, D.R. Christman, J.S. Fowler, T. Ido, R.R. MacGregor, P. Som, C.-N. Wan, A.P. Wolf, D.E. Kuhl, M. Reivich. "Radiopharmaceuticals XXVII: 18F-labeled 2-deoxy-2-fluoro-D-glucose as a radiopharmaceutical for measuring regional myocardial glucose metabolism in vivo: tissue distribution and imaging studies in animals", J. Nucl. Med. 18 990-996, (1977).
T. Ido, C.-N. Wan, V. Casella, J.S. Fowler, A.P. Wolf, M. Reivich and D. Kuhl, "Labeled 2-deoxy-D-glucose analogs. F-18 labeled 2-deoxy-2-fluoro-D-glucose, 2-deoxy-2-fluoro-D-mannose and C-14 2-deoxy-2-fluoro-D-glucose", J Labeled Compounds and Radiopharm. 14 175-184, (1978).
M. Reivich, D. Kuhl, A.P. Wolf, J. Greenberg, M. Phelps, T. Ido, V. Casella, J. Fowler, E. Hoffman, A. Alavi, P. Som and L. Sokoloff, "The 18F-fluorodeoxyglucose method for the measurement of local cerebral glucose utilization in man", Circ. Research 44 127-137 (1979).
Last Modified: June 28, 2012