I= ADIOLABELING, QUALITY CONTROL AND BIOLOGICAL EVALUATION OF PHENYL ALKYL OXIRANE CARBOXYLIC ACIDS
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Title of Thesis
ADIOLABELING, QUALITY CONTROL AND BIOLOGICAL EVALUATION OF PHENYL ALKYL OXIRANE CARBOXYLIC ACIDS

Author(s)
Hafiz Ghulam Abbas
Institute/University/Department Details
University Of The Punjab
Session
1992
Subject
Chemistry
Number of Pages
315
Keywords (Extracted from title, table of contents and abstract of thesis)
carboxylic acid, oxidant, fatty acids, lipid metabolism, radiopharmaceuticals, phenyl alkyl oxirane carboxylic acids, lipid metabolism

Abstract
Methods have been described for the synthesis. Purification and radio labeling of 2 €“ 15 €“ (4 €“ iodophenyl) pentyl ] oxirane-2-carboxylic acid (1 €“ pocA) and 2 €“ 16 €“ (4 €“ bromophenoxy) hexyl ] oxirane €“ 2 €“ carboxylic acid (Br €“ Etomoxir). For the synjthesis of these new agents, 5 €“ phenylpentyl bromide (1), synthesized from 5 €“ phenyl €“ 1 €“ pentanol using hydrobromic acid method, was converted to diethyl 5 €“ phenylpentyl malonato (2) where 6 €“ (4 €“ bromophenoxy) hexyl bromide (14), prepared by treating 4 €“ bromophenol with sodium hydroxide, was converted to diethyl 6 €“ (4 €“ bromophenoxy) hexyl malonate (15). Alkaline hydrolysis of the malonesters (2) and (15) afforded the corresponding monoesters, ethyl 5 €“ phenylpentyl malonate (3) and ethyl 6 €“ (4 €“ bromophenoxy) hexyl malonate (16). Para-substitution of iodine on the phenyl moiety of the monoester (3) was accomplished by the reaction of thallium trifluoroacetate (TTFA) and aqueous k1 yielding ethyl 5 €“ (4 €“ iodophenyl) pentyl malonate (4). 2 €“ methylene carboxylates, ethyl 7 €“ phenyl €“ 2 €“ methyleneheptanoate (5), ehyl7 €“ (4iodophenyl) €“ 2 €“ methylenjeheptanoate (6) and ethyl 8 €“ (4 €“ bromophenoxy) €“ 2 €“ methyleneoctanoate (17), synthesized from the monoesters (3), (4) and )16) respectively, on oxidation resulted in the 2 €“ oxirane carboxylates, ethyl 2 €“ (5 €“ (4 €“ iodophenypentyl] oxirane €“ 2 €“ carboxylate (8) and ethyl 2 €“ (6 €“ (4 €“ bromophenoxy) hexyl] oxirane €“ 2 €“ carboxylate (18) . the sodium salts of 2 €“ oxirane carboxylic acids. Sodium 2 €“ (5 €“ phenylpentyl) oxirane €“ 2 €“ carboxylate (9). Sodium 2 €“ (5 €“ (4 - iodphenyl] )oxirane €“ 2 carboxylate (10) and sodium 2 €“ 16 €“ (4 €“ bromophenoxy) hexyl] oxirane-2 €“ carboxylate (19) , synthesized by treating the corresponding 2-oxirane carboxylates with sodium hydroxide in the presence of tetrahydrofuran, were converted to 2- oxirane carboxylic acids, 2 €“ (5 €“ phenyl) oxirane 2- carboxylic acid (11), 2 €“ (5 €“ ( 4 €“ iodophenyl ) pentyl ] oxirane - 2 €“ carboxylic acid (12) and 2 €“ 16 (4 €“ bromophenoxy) hexyl oxirane €“ 2 €“ carboxylic acid (20) respectively.

Analytical techniques such as flash chromatography. Preparative thin layer chromatography (TLC), and preparative high performance liquid chromatography (HPLC), have been successfully applied for the purification of the synthesized compounds. Characterization of the synthesized non- radioactive compounds have been described employing the use of elemental analysis, infrared (1.R) spectroscopy, nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (ms).

The radio labeling procedures, based on the cu (1) ci €“ assisted isotopic exchange reaching reaction as well as thallation of the aromatic ring, have been developed. The methods resulted in a no- carrier-added and regiospecific radio iodination and radiobromination with high radiochemical yields. Methods for purification and characterization of 2- (5 €“ (4 €“ [1 3 1 / 1 2 3 1 ] iodophenyl) ] oxirane €“ 2 €“ carboxylic acid ([131 /123 1] poca ), 2 €“ [6 €“ (4 €“ [ 0 2 Br) bromohenoxy)] oxiranev €“ 2 €“ carboxylic acid ([ 0 2 br[ Et omoxir) and 2 €“ 16 €“ (4 - ] iodophenoxy) oxirane-2 €“ carboxylic acid ([ 131 1 ] etomoxor) using reversed phase HPLC have been described. Use of modern radioannlytical techniques, namely: radio- hplc and radio-tlc, for quality control (Q.C) of a new class of radiopharmaceuticals has been demonstrated. The reversed phase HPLC, used in the q.c af [131 1 ] POCA and [ 131 1] etomoxir, has been successfully applied to separate radio labeled substrates from different radioactive contaminants, to obtain highly purified products. To determine radiochemical yield, and radiochemical purity. HPLC, the most widely practiced from of liquid chromatography. has been successfully applied as a final radioanalyticl q.c test prior to appellation of radiopharmaceuticals for biological evaluation.

Automatic TLC linear analyzer, ideally suited to monitor the labeling process, has been employed for the radiochemical analysis. TLC linear analyzer (Berthold), equipped with a programmable EBM at personal computer, has been employed for data acquisition. The peak fitting, performed by the computer using chroma programme, permitted unfolding of overlapping peaks and resulted in an accurate representation of peak area. Automatic subtraction of background was possible and overlapping peaks were identified and quantified. The computer analysis, which was far beyond the limitations of conventional scanning methods, represented a dramatic improved and quick method of evaluating and viewing the raw data. TLC linear analyzer. Used to explore the effect of reaction conditions on labeling yield and to select the favorable reaction conditions, has been employed to analyze multiple samples in a single run and under the same chromatographic conditions. A method has been demonstrated for quick separation of radio labeled substrates from different radioactive contaminant, for determination of labeling efficiency, radiochemical yield, and radiochemical purity.

Pharmacokinetic data, obtained after i.v. injection of the radio labeled POCA to the male wistar rats, revealed reasonable uptake and long retention time in the kidneys and liver. On the basis of animal biodistribution data it is suggested that POCA, when labeled with 123 1 may act as a useful renal imaging agent and behave as a diagnostic tool in nuclear medicine. The pronounced uptake of [ 123 1] etomoxir in liver and spleen, minimal deiodination and raped blood clearance make this agent attractive for further evaluation in animals to measure metabolic activity of the liver and to assess the applicability of these new agents in nuclear medicine. The minimal thyroid radioactivity and low blood levels demonstrate that the attachment of the radioactive iodine to the phenyl /phenoxy ring was an effective means to stabilizing the iodine and overcoming the facile in vivo damage.

Download Full Thesis
2738.43 KB
S. No. Chapter Title of the Chapters Page Size (KB)
1 0 Contents
111.86 KB
2 1 Summary 8
74.08 KB
3 2 Introductions 13
707.57 KB
  2.1 Fatty Acids 14
  2.2 Relationship Between Lipid Metabolism And The Energy Balance Of Hear Muscle 14
  2.3 General Features Of The Control Of Fatty Acid And Lipid Metabolism 16
  2.4 Integrated Control Of Fatty Acid Metabolism 30
  2.5 History Of The Use Of Fa In Nuclear Medicine 36
  2.6 Positron Emission Tomography And Fa 47
  2.7 Autoradiography And Fa 51
  2.8 Pharmacological Properties Of Oxirane-2 €“ Carboxylic Acids 52
4 3 Synthesis Of Compounds Of Interest In Nuclear Medicine 70
352.29 KB
  3.1 General 71
  3.2 Methods 72
  3.3 Procedures For Synthesis 73
  3.4 Purification Of The Compounds 104
  3.5 Discussion 109
5 4 Radio Labeling Of Compounds 117
430.1 KB
  4.1 Radioisotopes Of Interest In Biological Research 118
  4.2 Methods Of Radiohalogenation 124
  4.3 Radio Labeling Procedures 133
  4.4 Discussion 145
6 5 Quality Control In Radiopharmaceuticals 157
632.18 KB
  5.1 Quality Control 158
  5.2 Chromatography 162
  5.3 Thin Layer Chromatography 172
  5.4 High Performance Liquid Chromatography ( Hplc ) 198
  5.5 Discussion 214
7 6 Biological Evaluation 226
384.51 KB
  6.1 Biodistribution Studies 227
  6.2 General Methods 229
  6.3 Details Of Animal Experimentation 230
  6.4 Results And Discussion 235
8 7 Conclusions 257
56.65 KB
  7.1 Achievements 258
  7.2 Future Prospects 261
9 8 Bibliography 263
323.29 KB