Relationship of molecular structure to the in vivo-distribution of carbon-11-labeled compounds. V. Carbon-11-labeled N-alkyl-p-iodobenzenesulfonamides.

Carbon 11-labeled HCN was collected in methanol containing carrier NaCN following bombardment of 99% N2-1% H2 with 22 MeV protons. Ten new N-alkyl-p-iodobenzenesulfonamides were synthesized and labeled with 11C in radiochemical yields averaging 27% by condensation of p-iodobenzenesulfonyl chloride with the 11C-labeled aliphatic amine obtained by reduction of the intermediate 11C-labeled aliphatic nitrile prepared from Na 11CN and the corresponding alkyl bromide. They were chemically characterized and for nine of them the relationship between their molecular structure and their in vivo-distribution in rats was studied. As the length of the alkyl chain was increased from 2 to 8 carbon atoms, the early concentration of activity in most viscera decreased and the urinary excretion increased. Within this range, chains containing an even number of carbon atoms showed greater early tissue concentration of activity than did chains containing an odd number of carbon atoms. For alkyl chains containing greater than 8 carbon atoms the concentration of activity in some tissues increased and urinary excretion decreased. A possible explanation for the results is offered which postulates that early tissue concentration of activity is related to both total lipophilicity of the sulfonamide as well as to the presence of tissue sulfonamide binding sites whose preferred conformation results in hindred binding of sulfonamides with odd-numbered aliphatic chains to a greater extent than with even-numbered aliphatic chains.

Liberation of cyanide from alpha-aminonitriles relative to amygdalin.

A series of aminoitriles have been synthesized and studied whose nonenzymatic dissociation with release of cyanide may be varied by modest alteration of their molecular structure from that obtained with nonenzymatic dissociation of amygdalin to that obtained from enzymatic dissociation of amygdalin by substantial quantities of beta-glucosidase. The relationship between such alterations in molecular structure and nonenzymatic dissociation is discussed. A combination of the results of these studies and studies relating molecular structure to physical localization propensity in tumors has potential in the design of chemotherapeutic agents.

Relationship of molecular structure to in vivo scintigraphic distribution of carbon-11-labeled compounds. 4. Carbon-11-labeled mandelonitriles, Mandelic acids, and their esters.

11C-Labeled HCN was collected in water containing carrier KCN following bombardment of 99% N2-1% H2 with 22 MeV protons. 11C-Labeled mandelonitrile and p-methoxy-, p-hydroxy-, and 3,4-dihydroxymandelonitrile were synthesized from K11CN and the corresponding benzaldehyde. The initial distribution of 11C activity of these nitriles in dogs was primarily in the region of the heart, liver, and kidneys followed by rapid redistribution to the parotids and stomach with [11C]hydroxymandelonitriles. 11C-Labeled mandelic acid and m-methyl-, o-chloro-, and p-chloromandelic acid were synthesized from the corresponding [11C]mandelonitrile. Serial scintigraphy of 11C activity of these mandelic acids in dogs showed progressive renal excretion with accumulation of activity in the bladder. 11C-Labeled ethyl and benzyl mandelate were synthesized from [11CA]mandelic acid. These esters showed initial accumulation of activity in the lungs with eventual excretion by the kidneys.

Relationship of molecular structure to in vivo scintigraphic distribution patterns of carbon-11 labeled compounds. 3. (11C)Hydantoins.

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.

Relationship of chemical structure and solvent to in vivo scintigraphic distribution patterns of 11C compounds. II. 11C aminonitriles.

The preparation and scintigraphic evaluation of the distribution patterns in dogs of a series of structurally related aminonitriles labeled with 11C is described. Carbon-11-HCN was collected in water containing carrier NaCN following 22 MeV proton bombardment of 99% N2 and 1% H2 gas mixture for 1 hr. Ten 11C alphaN-alkylaminophenylacetonitrile hydrochlorides and 12 11C alpha-N-arylaminoarylacetonitriles were prepared from 11C-NaCN and the corresponding Schiff base, Ar-CH=N-R(Ar). Those 11C aminonitriles that were administered intravenously in aqueous solution showed some initial accumulation of activity in the liver followed by diffuse whole-body distribution and some small accumulation in urine. Aqueous insoluble 11C aminonitriles, which were administered intravenously in ethanol, ether, or DMSO, showed variable initial partial retention of activity in the lungs with prominent accumulation of activity in liver and excretion in bile. Several of these compounds showed pronounced and rapid accumulation of activity in the brain. Such activity in the brain was largely cleared within 15 min. Concentration of activity in the cerebrospinal fluid following clearance from the brain was 30 times greater than blood and equivalent in concentration to that noted in bile 18 min after intravenous administration of 11C alpha-anilinophenylacetonitrile in ethanol. These results suggest the possible correlation of regional brain uptake of activity of certain 11C aminonitriles with regional brain perfusion. Use of these or similar materials could permit assessment of brain tissue morphology followed by scintigraphic imaging of the bulk flow characteristics of cerebrospinal fluid.