Degree Name

Doctor of Philosophy


Department of Chemistry - Faculty of Science


Three classes of compounds were chosen for investigation to find a high affinity and selective iodinated peripheral benzodiazepine receptor (PBR) ligand; indol-3-ylglyoxylamides, pyrazolopyrimidines, and pyridopyrrolooxazepines and pyrrolobenzoxazepines. These compounds were chosen from a literature search for their high PBR affinity and selectivity, ease of synthesis, and the potential for radioiodination.

Fifteen new halogenated N,N-dialkylindol-3-ylglyoxylamides were synthesised and tested for their PBR and central benzodiazepine receptor (CBR) affinity. The compounds IC50 values for the PBR ranged from 7.8 – 618 nM, and a structure activity relationship (SAR) was determined. Brominated compounds had higher binding affinities than their iodinated analogues, and indoles with a chloro substituent on position 5 had higher binding affinities than the non-chlorinated compounds. The optimum alkyl chain length was found to be two carbons. The highest affinity iodinated ligand, with a PBR IC50 of 8.2 nM, was radiolabelled with 123I in 55-60% radiochemical yield and evaluated in vivo in Sprague-Dawley rats. Biodistribution studies revealed high uptake of the radiotracer in organs known to contain PBR, such as the kidneys, adrenals, heart, liver and lungs. Drug competition studies showed that the PBR drugs PK11195 and Ro5-4864, when injected into the rat 5 min prior to injection of the radiotracer, significantly decreased uptake of radiotracer into those organs. The CBR drug, flumazenil, did not decrease the uptake of the radiotracer. Metabolite studies showed that the radiotracer was > 95% intact in the heart, kidneys, adrenals, and brain after 3 h and was 65% intact in the plasma. This compound is the first radiolabelled PBR ligand of this class, and is an excellent candidate for future studies and may lead to a clinically useful imaging agent.

Three pyrazolopyrimidines were synthesised, with lengths of the alkyl chains being methyl, ethyl, or propyl groups. The highest affinity ligand, with the propyl groups, displayed an IC50 of 7.9 nM, however, only the compound with ethyl groups displaying an IC50 of 11.7 nM was radiolabelled with 123I in 95% radiochemical yield, and evaluated in vivo in rats. This compound showed high uptake into organs known to contain PBR, and also showed an interesting result in which pre-administration of Ro5-4864 did not cause any significant decrease of uptake of radiotracer in the kidney or heart, however PK11195 did cause of significant decrease in these organs. This compound provides the first radioiodinated PBR ligand of this class.

Two pyrrolopyridooxazepines and two pyrrolobenzoxazepines were synthesised and tested. One of the compounds was found to be inactive, while the others had moderate PBR IC50 values of 24-39 nM. The moderate binding affinity for these compounds would unlikely lead to a successful imaging agent.

02Whole.pdf (1350 kB)