Unsymmetrical alkyl aryl thiourea compounds for use as cerebral blood flow tracers

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Abstract
The synthesis and characterization of an homologous series of inert nonvolatile 14C-labeled unsymmetrical alkyl aryl thiourea compounds is described for their use as regional cerebral blood flow (rCBF) tracers employing autoradiographic procedures. In alert normocapnic rats the single-pass extraction values into brain for these thioureas were dependent on their respective lipid solubilities ranging 0.497 for 1-methyl-3-phenylthiourea to 0.730 for 1-butyl-3-phenylthiourea. The commonly used rCBF tracers, [14C]antipyrine and [14C]iodoantipyrine had single-pass extraction values of 0.451 and 0.553, respectively. The single-pass extraction value for n-butanol was the same as that for 1-butyl-3-phenylthiourea; n-butanol and 1-butyl-3-phenylthiourea are mildly diffusion limited at normal rates of flow in rat brain. Since 1-butyl-3-phenylthiourea diffused most readily into rat brain it was chosen as a potentially valuable rCBF tracer. Its brain-blood partition coefficient was 1.09. The plasma distribution of this thiourea in blood varied inversely with the hematocrit and the compound was freely exchangeable between plasma and erythrocytes. Employing 1-butyl-3-phenyl-thiourea to measure rCBF and its empirically derived brain extraction values, the following flow rates in normocapnic rats were found: 3.2 ml/g per min for cochlear nucleus; 3.0 for inferior colliculus; 2.5 for medial geniculate; 1.9 for pontine gray and hypothalamus; 1.7 for caudate and cerebral cortex; and 1.2 for cerebellar gray and 0.41-0.50 for white matter structures. 1-Butyl-3-phenylthiourea is more advantageous than iodoantipyrine for measuring rCBF, especially in those areas that possess very rapid rates of flow.

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