Bone Accumulation of the Tc-99m Complex of
In sickle-cell disease, red-cell deformation can oc
cur at low oxygen tensions. The mechanism appears
related to intramolecular bonding within hemoglo
bin S. One approach to the prevention of this bond
ing has been the attempted chemical modification
of hemoglobin by use of agents such as carbamyl
phosphate (1 ,2). In 1976 we therefore began a pro
gram to investigate the binding of Tc-99m by car
bamyl phosphate. The resultant complex turned out
to be a bone-seeking agent. Carbamyl phosphate
[H2N .CO . OPO . (OH)2] contains but a single phos
phate group as contrasted with the two phosphates
or phosphonates in currently used bone-imaging
agents such as pyrophosphate, imidodiphosphate
and diphosphonate. We therefore constructed a
working hypothesis to indicate which groupings on
the carbamyl phosphate molecule were necessary for
the bone affinity of the Tc-99m complex. This hy
pothesis was tested by studying a series of analogs.
MATERIALSAND METHODS
The disodium salt of carbamyl phosphate, amino
methylphosphonic acid, and phosphoenolpyruvate
were used as obtained commercially. Acetyl phos
phate was purchased as the mixed lithium-potassium
salt; the latter ions were exchanged for hydrogen be
fore use by means of a 50W-X2 resin5. Propionyl
phosphate and butyryi phosphate were synthesized
from silver phosphate and the corresponding acid
chloride by the method of Lipmann and Tuttle (3).
The compounds were used directly as the silver salts.
The chemicals were labeled with Tc-99m in the
presence of stannous chloride. A solution of the corn
pound of interest (0.1 % by weight in isotonic saline)
was mixed with stannous chloride solution (0.1 % by
weight in 0. iN H@) in the ratio of 10: 1. The pH
of the product was adjusted between S and 6. It was
then purged with nitrogen gas and finally passed
through a 0.22-@&mfilter. To 1 ml of the resultant
solution was added 1 ml of the eluate of a pertech
netate generator that contained 1—30mCi of radio
Received July 25, 1977; revision accepted Dec. 20, 1977.
For reprints contact: Richard P. Spencer, Dept. of Nuclear
Medicine, University of Connecticut Health Ctr., Farming
ton, CT 06032.
530 THE JOURNAL OF NUCLEAR MEDICINE
Carbamyl Phosphate and Its Analogs
Parvathi Hosain, Richard P. Spencer,Karen J. Ahlquist, and Pavanaram K.Sripada
University of Connecticut Health Center, Farmington, Connecticut
Carbamyl phosphate, an organic molecule containing a single phosphate
group, has been used in the therapy oJ sickle-cell disease. Carbamyl phos
phate bound Tc-99m and achieved bone uptake in mice, rabbits, and a
human volunteer. By examination of the structural formula, a working
hypothesis was developed that predicted that the Tc-99m complexes of the
analogous compounds acetyl phosphate, propionyl phosphate, and butyryl
phosphate, each carrying single phosphate and carbonyl groups, would also
show bone specificity. This was confirmed experimentally. Phosphonoacetic
acid is a structural analog of these compounds. The structural analysis
also predicted that aminomethylphosphonic acid and phosphoenolpyruvate
would not have as avid bone affinity, and this was also confirmed. These
compounds represent a new class of bone-seeking agents that have the com
mon properties of a lone phosphate and a carbonyl function. Such agents
may permit the synthesis of additional analogs in an effort to obtain optimal
affinity in the Tc-99m complexes.
J Nuci Med 19: 530—533,1978
