William R. Banks

A trap for the removal of nitrogen oxides from carbon-11 carbon dioxide

Abstract A trap is described that removes the nitrogen oxides from [ 11 C]carbon dioxide. This improves the yields of the subsequent reactions of the carbon dioxide and permits the use of much smaller amounts of reagents, which should improve the specific activities of the final products.

Radiosynthesis of a 11C-labelled benzodiazepine receptor agonist : 1-[11C]alprazolam

Abstract The benzodiazepine receptor agonist, alprazolam ( 3 ) has been successfully labelled with carbon-11 in a metabolically stable position. Reaction of the amidrazone, 7-chloro-5-phenyl-3H-1,4-benzodiazepine-2-yl hydrazine ( 1 ), with 1-[ 11 C]acetyl chloride followed by pyrolysis of the resulting 1-acetyl-hydrazine 2 afforded the title compound 1-[ 11 C]alprazolam in 43–65% yield, in 40–55 min at specific activities of 0.93–2.18 Ci/μmol. The straightforward synthesis herein reported lends itself well to a useful remote controlled synthesis.

Studies with [11C]alprazolam: an agonist for the benzodiazepine receptor

We have built a system for the synthesis of high specific activity carbon-11 alprazolam (Xanax), a high affinity agonist for the benzodiazepine receptor. The system produces 30-40 mCi of the compound with a specific activity of > 12,000 Ci per millimole. Using this compound we have performed PET studies on 6 normal subjects and studied the cerebral influx and efflux of the compound. The uptake in the brain was low, approx. 1% of the administered dose. However, the levels of the compound in the circulation at early time points are heavily affected by the specific activity of the tracer, i.e. when pharmacologically active doses are used as blocking doses the concentration of radioactive material is higher in the circulation and more material enters the brain. We attribute this to a depot effect where the compound is trapped in saturatable sites in an organ, probably the lungs, and is slowly released over time. In the presence of blocking doses of agonist, the compound washes out of the brain more quickly suggesting that some blockade of the receptors is occurring. However, the pharmacological activity of the compound does not permit the administration of enough material to ensure complete receptor blockade. The compound shows definite signs of acting as a receptor binding ligand but the unusual pharmacokinetics complicate the interpretation of the data.

Development of methodology for the rapid incorporation of carbon-13 into 1,2,4-triazolo systems from carbon dioxide

An in situ production of C-13 acetyl chloride and subsequent reaction with amidrazones affords anxiolytic 1,2,4-triazolobenzodiazepines in reaction times suitable for labelling with carbon-11 (t12=20.4 min).

Peptidyl Carbamates as Human Leukocyte Elastase Inhibitors: Design and Synthesis of Desmosine-Like Tetrapeptidyl Carbamate Inhibitors

AbstractThe rational design and synthesis of a series of peptidyl carbamates incorporating a derivatized ornithyl or lysyl residue at the P3 or P4 subsite is described. The derivatized residues were chosen as mimics of desmonsine cross-links ubiquitously found in mature elastin. The alteration of specific residues of the peptidyl carbamate, in addition to the realization of a stereospecific synthesis, required utilization of two convergent synthetic approaches. When tested for inhibitory activity against the serine dependent enzymes, human leukocyte elastase, porcine pancreatic elastase, trypsin, chymotrypsin, as well as acetyl cholinesterase, the compounds were found to be specific inhibitors of the elastases. Thus the series was found to exhibit inhibitor dissociation constants as low as 0.2 × 10−6M and 3.0 × 10−6M for human leukocyte and porcine pancreatic elastase, respectively. Michaelis-Menten kinetics demonstrated active site inhibition. Placement of Nδ-Bz-L-Orn at P4 withp-nitrophenol at P1’(23a) ...

Tritiated and deuterated alprazolam. The use of deuterium NMR to study isotope exchange in tritiated alprazolam

Abstract Using labeled acetate, tritium was incorporated into the triazolomethyl group of alprazolam, a triazolobenzodiazepine. During chemical synthesis, purification and storage, a rapid loss of tritium into solvent media was noted. As a model reaction using tritiated sodium acetate (sp. act. 0.1 Ci/mmol), tritiated alprazolam was produced in 92% chemical yield (19% radiochemical yield) exhibiting a sp. act. of 0.02 Ci/mmol. Investigation of the lability of the α-methyl tritia utilized the synthesis of deuterated alprazolam and deuterium NMR. Deuterated alprazolam was found to exchange with all buffer systems employed over the pH range 1–11. The exchange was shown to be a rapid ( t 1 2 ∼ 2.5 min ) process which appeared to proceed independently of pH.