1-Azabicyclo[2.2.2]oct-3-yl alpha-hydroxy-alpha-(1-iodo-1-propen-3-yl)- alpha-phenylacetate (IQNP, 1), is a highly selective ligand for the muscarinic acetylcholinergic receptor (mAChR). There are eight stereoisomers in the racemic mixture. The optical isomers of alpha-hydroxy-alpha-phenyl-alpha-(1-propyn-3-yl)acetic acid were resolved as the alpha-methylbenzylamine salts, and the optical isomers of 3-quinuclidinol were resolved as the tartrate salts. The E and Z isomers were prepared by varying the reaction conditions for the stannylation of the triple bond followed by purification utilizing flash column chromatography. In vitro binding assay of the four stereoisomers containing the (R)-(-)-3-quinuclidinyl ester demonstrated that each isomer of 1 bound to mAChR with high affinity. In addition, (E)-(-)-(-)-IQNP demonstrated the highest receptor subtype specificity between the m1 molecular subtype (KD, nM, 0.383 +/- 0.102) and the m2 molecular subtype (29.6 +/- 9.70). In vivo biodistribution studies demonstrated that iodine-125-labeled (E)-(-)-(+)-1 cleared rapidly from the brain and heart. In contrast, iodine-125-labeled (E)-(-)-(-)-, (Z)-(-)-(-)-, and (Z)-(-)-(+)-1 have high uptake and retention in mAChR rich areas of the brain. It was also observed that (E)-(-)-(-)-IQNP demonstrated an apparent subtype selectivity in vivo with retention in M1 (m1, m4) mAChR areas of the rain. In addition, (Z)-(-)-(-)-IQNP also demonstrated significant uptake in tissues containing the M2 (m2) mAChR subtype. These results demonstrate that the iodine-123-labeled analogues of the (E)-(-)-(-)- and (Z)-(-)-(-)-IQNP isomers are attractive candidates for single-photon emission-computed tomographic imaging of cerebral and cardiac mAChR receptor densities.
The imidazole nucleosides, 4(5)‐bromo‐5(4)‐nitro‐1‐β‐D‐ribofuranosylimidazoles, have been prepared via glycosylation of the trimethylsilylated aglycone, 4(5)‐bromo‐5(4)‐nitroimidazole, with tetra‐O‐acetyl‐β‐D‐ribo‐furanose followed by removal of the acetyl protecting groups. The 5‐bromo‐4‐nitro‐1‐β‐D‐ribofuranosylimidazole nucleoside was acetonated to produce 5‐bromo‐4‐nitro‐1‐(2,3‐O‐isopropylidene‐β‐D‐ribofuranosyl)‐imidazole which was cyclized to provide the corresponding anhydronucleoside 5,5′‐anhydro‐4‐nitro‐5‐oxo‐1‐(2,3‐O‐isopropylidene‐β‐D‐ribofuranosyl)imidazole. Sodium hydrosulfide treatment of 5‐bromo‐4‐nitroimidazole nucleoside provided 5‐mercapto‐4‐nitro‐1‐β‐D‐ribofuranosylimidazole 5‐sodium salt which was alkylated with E‐1,5‐diiodopent‐1‐ene to yield 5‐(E‐1‐iodo‐1‐penten‐5‐yl)thio‐4‐nitro‐1‐β‐D‐ribofuranosylimidazole. The corresponding iodine‐125‐labeled compound was prepared similarly using radiolabeled diiodopentene. The 5‐bromo‐4‐nitroimidazole, 5‐mercapto‐4‐nitroimidazole, and 5‐iodopentenylthio‐4‐nitroimidazole nucleosides were cytotoxic to Molt‐3 cells in vitro at concentrations higher than 10 μg/mL. The radiolabeled 5‐iodopentenylthio‐4‐nitroimidazole nucleoside showed 2‐fold higher uptake in a rapidly growing tumor as compared to uptake in a relatively slower growing tumor in mice.
Introduction of geminal dimethyl-branching into the 3-position of 15-(p-iodophenyl) pentadecanoic acid (IPPA) significantly delays myocardial clearance in rats and dogs following intravenous administration. Several new analogues of DMIPP have been synthesized and evaluated in fasted rats. The effects of both the position of dimethyl-branching and the total chain-length of 3, 3-dimethyl analogues on heart uptake and clearance kinetics have been studied. In the first series of compounds, two methyl groups were introduced into the 3-, 4-, 6-, or 9- position. Tissue distribution studies of the 15-(p-[I-125] iodophenyl)-analogues demonstrated that the position of dimethyl-branching is an important factor affecting both myocardial specificity and retention. The [I-125] labeled 3,3- and 4,4-DMIPP analogues showed higher myocardial uptake and faster blood clearance than the 6,6- and 9,9-DMIPP analogues [heart, % dose/gm heart: blood), 30 min: 3,3-DMIPP = 5.06 (12:1); 4,4-DMIPP = 8.03 (16.7: 1); 6,6-DMIPP = 2.26 (3.1:1); 9,9-DMIPP = 3.06 (2.77)]. In the second series, the effects of total fatty acid chain length were evaluated with 3,3-dimethyl-substituted analogues with C11, C12, C13, C14, C15, and C19 chain lengths. The C14 and C15 chain length analogues showed the best properties [global heart: blood ratios): 30 min: C11, 0.70 (0.82); C12, 1.25 (0.68); C13, 0.47 (0.90); C14, 1.63 (3.54); C15, 5.06 (12); C19. 1.29 (0.82). These detailed studies have demonstrated that both total chain length and the position of geminal dimethyl-branching are important structural parameters which affect myocardial specificity and retention of omega-(p-iodophenyl)-substituted fatty acid analogues and that 3,3-DMIPP and 4,4-DMIPP are the best candidates with optimal properties for further study.
E-(R,R)-IQNP is a new ligand analogue of IQNB, which has high affinity for the cholinergic-muscarinic receptor. Earlier studies have demonstrated high cerebral uptake of activity with selective localization in M1 receptor subtype areas of the brain. In this paper we describe the results of metabolic studies of E-(R,R)-IQNP directed at determining the metabolic fate of this ligand and the identification of the radioactive species observed in the brain and heart tissue. Tissue Folch extracts demonstrated that the lipid-soluble extracts from brain contained 87.0% +/- 1.65% of the activity up to 24 h. In the heart, 61.9% +/- 7.50% of the activity was extracted in the lipid-soluble extract after 30 min, decreasing to 51.4% +/- 0.65% by 4 h. In contrast, data from other tissues studied demonstrated large amounts of either aqueous soluble activity or activity which was not extracted from the tissue pellet material; analysis of lipid organic extracts revealed the following results: liver (4 h), 7.43% +/- 0.96%; serum (4 h), 3.73% +/- 0.87%; urine (24 h), 9.4%; feces (24 h), 16.5%. Thin-layer chromatographic (TLC) and high-performance liquid chromatographic (HPLC) analyses of lipid-soluble brain extracts indicated that only unmetabolized E-(R,R)-IQNP was detected (99.4% +/- 1.25%). Activity which was extracted into the organic phase from heart tissue was also determined by TLC and HPLC analysis to contain large amounts of unmetabolized ligand after 4 h (88.5% +/- 0.57%). In addition, however, low levels of two additional radioactive components were detected which increased with time. TLC analysis of the plasma lipid extracts indicated only a small amount of unmetabolized E-(R,R)-IQNP.(ABSTRACT TRUNCATED AT 250 WORDS)
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