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We have developed an efficient synthesis method for the rapid and high‐yield automated synthesis of 4‐(2′‐methoxyphenyl)‐1‐[2′‐(N‐2″‐pyridinyl)‐p‐[18F]fluorobenzamido]ethylpiperazine (p‐[18F]MPPF). No‐carrier‐added [18F]F−was trapped on a small QMA cartridge and eluted with 70% MeCN(aq) (0.4 mL) containing Kryptofix 222 (2.3 mg) and K2CO3(0.7 mg). The nucleophilic [18F]fluorination was performed with 3 mg of the nitro‐precursor in DMSO (0.4 mL) at 190 °C for 20 min, followed by the preparative HPLC purification (column: COSMOSIL Cholester, Nacalai Tesque, Kyoto, Japan; mobile phase: MeCN/25 mmAcONH4/AcOH = 200/300/0.15; flow rate: 6.0 mL/min) to afford p‐[18F]MPPF (retention time = 9.5 min). p‐[18F]MPPF was obtained automatically with a radiochemical yield of 38.6 ± 5.0% (decay corrected, n= 5), a specific activity of 214.3 ± 21.1 GBq/µmol, and a radiochemical purity of >99% within a total synthesis time of about 55 min. Copyright © 2012 John Wiley & Sons, Ltd.

Two epimeric bile acid conjugates, 5-aminosalicylic acid-chenodeoxycholic acid (5-ASA-CDCA) and 5-aminosalicylic acid-ursodeoxycholic acid (5-ASA-UDCA), were synthesized to deliver 5-ASA to the large intestine by oral administration. The movement of the conjugates down the gastrointestinal tract and the anti-inflammatory effects on ulcerative colitis were investigated by administering the conjugates to guinea-pigs with an inflammatory bowel disease induced by 2% degraded carrageenan solution. The conjugates were protected from deconjugation in stomach and small intestine and reached the caecum and the colon, where 5-ASA was more easily liberated from 5-ASA-CDCA than from 5-ASA-UDCA. The conjugates at doses equivalent to 50 or 150 mg kg−15-ASA were orally administered once a day for 4 weeks from the 15th day after starting carrageenan treatment. The body weights and the bleeding scores of occult blood in faeces were measured during the experiment. The number of ulcers in the caecum and the colon were counted after killing the guinea-pigs at the end of the experiment. Rapid onset of efficacy was shown by a significant reduction in bleeding scores within a week after administration of the conjugates. Treatment with the lower dose of 5-ASA-CDCA showed a recovery of body weight and a significantly decreased number of ulcers in the caecum, and the ulcers in the colon had completely disappeared by the end of the experiment. There was a good correlation found between the number of ulcers in the caecum and the bleeding scores of occult blood in faeces. The findings indicate that both conjugates were sufficiently delivered to the large intestine without deconjugation and that the lower dose of 5-ASA-CDCA is enough for treatment of ulcerative colitis in colonic inflammatory bowel diseases.

Two epimeric bile acid conjugates, 5‐aminosalicylic acid‐chenodeoxycholic acid (5‐ASA‐CDCA) and 5‐aminosalicylic acid‐ursodeoxycholic acid (5‐ASA‐UDCA), were synthesized to deliver 5‐ASA to the large intestine by oral administration. The movement of the conjugates down the gastrointestinal tract and the anti‐inflammatory effects on ulcerative colitis were investigated by administering the conjugates to guinea‐pigs with an inflammatory bowel disease induced by 2% degraded carrageenan solution. The conjugates were protected from deconjugation in stomach and small intestine and reached the caecum and the colon, where 5‐ASA was more easily liberated from 5‐ASA‐CDCA than from 5‐ASA‐UDCA. The conjugates at doses equivalent to 50 or 150 mg kg−15‐ASA were orally administered once a day for 4 weeks from the 15th day after starting carrageenan treatment. The body weights and the bleeding scores of occult blood in faeces were measured during the experiment. The number of ulcers in the caecum and the colon were counted after killing the guinea‐pigs at the end of the experiment. Rapid onset of efficacy was shown by a significant reduction in bleeding scores within a week after administration of the conjugates. Treatment with the lower dose of 5‐ASA‐CDCA showed a recovery of body weight and a significantly decreased number of ulcers in the caecum, and the ulcers in the colon had completely disappeared by the end of the experiment. There was a good correlation found between the number of ulcers in the caecum and the bleeding scores of occult blood in faeces. The findings indicate that both conjugates were sufficiently delivered to the large intestine without deconjugation and that the lower dose of 5‐ASA‐CDCA is enough for treatment of ulcerative colitis in colonic inflammatory bowel diseases.

Multiple types (structures) of inclusion complexes between barbiturates and 2-hydroxypropyl-β-cyclodextrin (HPCD) were evaluated by isothermal titration microcalorimetry and ¹³C NMR spectroscopy. The geometries of the inclusion complexes were suggested by molecular dynamics simulation. Barbituric acid (BA), barbital (B), amobarbital (AB), pentobarbital (PB), secobarbital (SB), cyclobarbital (CB), and phenobarbital (PHB) were used as barbiturates with different substituents on the barbituric acid ring and compared for inclusion types in aqueous solution. The association constants (K), stoichiometries, and thermodynamic parameters change in free energy (ΔG) change in enthalpy (ΔH), and change in entropy [ΔS] for each type of complex were determined from the calorimetric data. The inclusion complexation was largely entropy driven because of hydrophobic interactions. The values of K increased in the order BA<B<AB<PB<SB<CB<PHB. Barbiturates, except B and BA, form two types of inclusion complex with a 1:1 stoichiometry in the un-ionized forms. The first type of inclusion complex with high affinity (K1) was characterized by small negative values of ΔH1 and large positive ΔS1, where the substituent R2 of the barbiturate was initially inserted into the cavity of HPCD through hydrophobic interactions. There was a good relationship between ΔG1 obtained from the calorimetric data for the first type of inclusion complex and ΔGR2 calculated from the changes in ¹³C Nuclear Magnetic Resonance (NMR) chemical shifts for the substituent R2 of barbiturates. These types were very stable in aqueous solution at various pHs. The second type of complex, with low affinity (K2), was characterized by large negative values of ΔH2 and small positive ΔS2, reflecting van der Waals' interactions in the un-ionized forms of barbiturates at pH values less than pKa. The values of K2 were markedly decreased to <10³ M⁻¹ as the barbiturates were ionized over pH 8. Thus, in the second type, the barbituric acid ring contributed to forming the complexes. The geometries were stabilized by hydrogen bond formation between the hetero atoms in the barbituric acid ring and the secondary hydroxyl groups on the rim of the cyclodextrin. The ¹³C NMR chemical shifts of C4 and C6 carbons in the barbituric acid ring were moved upfield significantly by the inclusion complexation. On the other hand, B and BA could form only one type of complex, the lid-type supramolecular complex with small association constants. © 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:1186–1197, 2001

Multiple types (structures) of inclusion complexes between barbiturates and 2‐hydroxypropyl‐β‐cyclodextrin (HPCD) were evaluated by isothermal titration microcalorimetry and 13C NMR spectroscopy. The geometries of the inclusion complexes were suggested by molecular dynamics simulation. Barbituric acid (BA), barbital (B), amobarbital (AB), pentobarbital (PB), secobarbital (SB), cyclobarbital (CB), and phenobarbital (PHB) were used as barbiturates with different substituents on the barbituric acid ring and compared for inclusion types in aqueous solution. The association constants (K), stoichiometries, and thermodynamic parameters change in free energy (ΔG) change in enthalpy (ΔH), and change in entropy [ΔS] for each type of complex were determined from the calorimetric data. The inclusion complexation was largely entropy driven because of hydrophobic interactions. The values of Kincreased in the order BA

Ion-pair complexes of 3-dl-α-tocopherylcarbonyl-1-hexyl pyridinium-[¹⁴C]-labeled cromolyn and 3-d-α-[5-methyl-³H] tocopherylcarbonyl-1-hexylpyridinium-cromolyn have been prepared with radiochemical yields of 56·0 and 65·7%, respectively. Copyright © 2000 John Wiley & Sons, Ltd.

Binding sites on human serum albumin (HSA) for anionic drugs and fatty acids have been thermodynamically characterized by microcalorimetry. The binding and the thermodynamic parameters were directly computed from the calorimetric titration data at 37°C in a phosphate buffer (pH 7.4) using one‐ and two‐class binding models. From compensation analyses plotting the molar enthalpy change (ΔHm,i) versus those of the molar free energy (ΔGm,i) and molar entropy (ΔSm,i) for each class of binding sites, HSA binding sites were classified into groups S1, S2, and S3. Group S1 included high‐affinity binding sites for site II‐bound drugs, such as ibuprofen, flufenamic acid, and ethacrynic acid, and short‐ or medium‐length alkyl‐chain fatty acids; group S2 included low‐affinity binding sites of site II‐bound drugs and long‐length alkyl‐chain fatty acids; and group S3 contained the high‐affinity binding sites for site I‐bound drugs, such as phenylbutazone, oxphenbutazone, and warfarin, and long‐length alkyl‐chain fatty acids. High‐ and low‐affinity bindings sites for salicylic acid and acetylaslicylic acid agreed with the regions of groups S3 and S2, respectively. Groups S1 and S2 were characterized by large negative values of ΔHm,iand ΔSm,i, reflecting van der Waals interaction and hydrogen‐bonding formation in low dielectric media, and the main force to stabilize the binding complex in group S3 was a hydrophobic interaction, characterized by a small negative ΔHm,iand minor or positive values of ΔSm,i(entropy‐driven).