Relation of molecular structure to in vivo scintigraphic distribution patterns of carbon-11-labeled compounds. 3. Carbon-11-labeled hydantoins

Abstract

The preparation and gamma-scintigraphic evaluation of the in vivo distribution patterns in dogs of a series of structurally related hydantoins labeled with the positron emitting, 20.4 min half-life radionuclide, carbon-11 are described. Carbon-11 labeled HCN was collected in water or aqueous Me2SO containing carrier KCN following cyclotron bombardment of 99% N2-1% H2 gas mixture with 22 MeV protons for 1 hr at 25-35 muA. Five 11C-labeled 5,5-dialkylhydantoins, three [11C]diarylhydantoins, five [11C]-5-alkyl-5-phenylhydantoins, and five [11C]spirohydantoins were prepared by heating generally under pressure, a mixture of 11C-labeled KCN, which was produced by isotopic exchange with carrier KCN, the corresponding aldehyde or ketone, and excess (NH4)2CO3 in aqueous ethanol or Me2SO solvent. The 11C-labeled hydantoins were dissolved in 1-1.5% aqueous NaOH for intravenous administration to dogs. Total synthesis time was 70-106 min and 1-59 mCi of final product was available for conducting serial in vivo imaging for up to 2 hr or more with the gamma-scintillation camera. Carbon-11 activity from all compounds showed initial blood-pool distribution with variable concentration of activity in the brain, lungs, liver, and kidney. All of the 11C-labeled diarylhydantoins, and most having one phenyl substituent, and one having a hexamethylene moiety showed initial accumulation of 11C activity in brain. Carbon-11 labeled 5,5-diphenylhydantoin (dilantin) showed the greastest qualitative accumulation of activity in the brain. Those 11C-labeled hydantoins having a carboxyl substituent showed prominent renal concentration and urinary excretion of activity. Most 11-c-labeled hydantoins showed a progressive homogenous whole body distribution of activity in all cellular tissues of the body. The relatively uniform distribution of activity in cellular tissues and slow excretion from the body support the thesis that the pharmacologic action of the hydantoins is related to physical effects on biomembranes rather than to specific chemical interactions with cell constituents.

11CO bonds made easily for positron emission tomography radiopharmaceuticals

“…Substituted ureas, including hydantoins such as the anticonvulsant [ 11 C]phenytoin, underwent extensive preclinical evaluation to determine biodistribution and to evaluate their potential as radiotracers. 180,181 It is now known that [ 11 C]phenytoin is a weak P-glycoprotein substrate, and may have utility in reporting on the activity of this efflux pump. 198 …”

Brain uptake and metabolism of [1-11C]octanoate in rats: Pharmacokinetic basis for its application as a radiopharmaceutical for studying brain fatty acid metabolism

“…[1-"C}Octanoic acid was synthesized by a Grignard reaction of "COZ with heptyl magnesium bromide, 12,11 in an automated synthesis apparatus (Yajima K et al, J. Automatic Chem., in press).…”

Synthesis, NMR analysis and applications of isotope-labelled hydantoins

“…Use of the simplest aldehyde formaldehyde in this reaction does give hydantoin (1), but also other products including hydantoic acid and hydantoic amide [70]. Work by Winstead et al [71] nicely demonstrates the range of aliphatic, aromatic and cyclic substituted hydantoins that can be produced by the Bucherer-Bergs reaction, which in this case were labelled with the positron emitting carbon-11 at the 4-position by using [ 11 C]potassium cyanide in the reaction (Figure 3, Scheme 3). The 11 C-labelled hydantoins prepared here were used to measure their in vivo tissue distribution pattern in dogs.…”