الفهرس 
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Abstract
Summary
Preparation of some radiolabeled pharmaceutical compounds
of expected biological activity
The human brain is the command center for the human nervous system. It receives input from the sensory organs and sends output to the muscles. There are many several receptors on the brain receptors that have a prominent role in brain function, as they are the effector sites of neurotransmission at the postsynaptic membrane, have a regulatory role on presynaptic sites for transmitter reuptake and feedback and are modulating various functions on the cell membrane. Distribution, density and activity of receptors in the brain can be visualized by radioligands labeled for SPECT and PET. selective radioligands are available for the various transmitter systems by which the distribution of these receptors in the normal brain and changes in receptor binding during various physiologic activities or resulting from pathologic conditions can be visualized.
The aim of this thesis is to develop potential selective radiopharmaceuticals for the non-invasive brain imaging. The selection of the proper isotope to be used in labeling and in imaging is important because it should have a suitable short half-life to avoid unwarranted harmful exposure to radiation and suitable photon energy within the range of gamma camera. The measurement of regional cerebral blood flow (rCBF) by single-photon emission computed tomography (SPECT) represents the most commonly available and widely applied functional brain imaging technique used in clinical practice. Several recent reviews describe the use of SPECT alone or in combination with PET and/or functional magnetic resonance imaging (fMRI) in studies of human cognition, imaging of neuroreceptor systems, in aiding diagnosis or assessment of progression or treatment response in various psychiatric and neurologic disorders. Brain SPECT is now commonly used in diagnosis, prognosis assessment, evaluation of response to therapy, risk stratification, detection of benign or malignant viable tissue and choice of medical or surgical therapy, especially in head injury, malignant brain tumors, cerebrovascular disease, movement disorders, dementia and epilepsy.
Radiopharmaceuticals consist of radioactive isotope and pharmaceutical ligand reliable as a carrier the radioactive isotope through their accumulation in a specific organ of the body depending on the pharmacological properties. The radioisotope, which in turn will emit the radiation required for the diagnosis or treatment process depending on the nuclear properties. Diagnostic radiopharmaceuticals require some of the characteristics to show high efficiency in diagnosis, including: ease of preparation, the short half-life, only gamma rays emission and the efficiency of their accumulation in the organ of interest (high T/NT ratio).
When formulating radiopharmaceuticals, a number of factors must be taken into consideration such as particle size of the resulting formulated radiopharmaceutical compounds, the degree of plasma protein binding and the melting point, as well as the efficiency of its biological distribution, since these compounds are used in the diagnosis and treatment of many diseases, the testing of quality control, such as measuring the degree of chemical purity, the degree of radiochemical purity, radionuclidic purity, sterility, pyrogenicity free and biodistribution to make sure that the purity, safety and efficiency of these products for desired application in nuclear medicine is of great importance. The choice of radioisotope suitable for use in the preparation of radiopharmaceutical, at least as important as choosing the pharmaceutical ligand itself, which should provide proper conditions, its physical half life is short enough to save the patient from high radiation dose and long enough to carry out labeling and scintigraphic measurements and it should has photon energy for this radioisotope suitable for appropriate imaging with gamma camera. 99mTc and 123I are radioisotopes that fulfill these requirements and choosing any of them depends on the chemical structure of the compound to be labeled.
This thesis consists of two chapters:
• Chapter I: Optimization of CNS active radiopharmaceuticals.
• Chapter II: Preparation of different IN formulations of radiopharmaceuticals and study of their biodistribution.
Following is a brief description of contents of each chapter.
• Chapter I: Optimization of CNS active radiopharmaceuticals
Include labeling of haloperidol and trazodone using 125I via direct electrophilic substitution reaction and studying the factors that affect their % labeling yield. It also include labeling of phenobarbital with 99mTc via direct labeling technique using stannous chloride as a reducing agent and studying the factors affecting % labeling yield of 99mTc-phenobarbital.
1) For iodo compounds the factors were substrate amount, Chloramine-T amount, pH, temperature, reaction time and in vitro stability of iodo compounds.
2) For technetium labeled compound the factors were substrate amount, stannous chloride amount, pH, temperature, reaction time and in vitro stability of technetium labeled compound.
We can summarize results in the following points:
- Trazodone was labeled with 125I and gave maximum % labeling yield of 91.23±2.12 % at 300 µg TZ, 20 µg CAT, pH 4 and 45 mins reaction time at room temperature.125I-TZ was stable up to 6 hrs with % labeling yield of 89.00±1.65 % at 6 hrs.
- Haloperidol was labeled with 125I and gave maximum % labeling yield of 93.42±1.53 % at 500 µg HP, 10 µg CAT, pH 6 and 45 mins reaction time at 60 ⁰C. 125I-HP was stable up to 24 hrs with radiochemical yield of 92.17±1.00 % at 24 hrs.
- Phenobarbital was labeled with 99mTc and gave maximum % labeling yield of 94.42±1.26 % at 25µg PB, 15µg Sn (II), pH 7 and 30 mins reaction time at 70 ⁰C. 99mTc-PB was stable up to 2 hrs with a maximum % labeling yield 91.23±1.2 % at 2 hrs.
• Chapter II: Preparation of different IN formulations of radiopharmaceuticals and study of their biodistribution:
• Deals with biological evaluation of these labeled complexes using male albino Swiss mice, evaluation of their brain uptake by intravenous and intranasal injection comparing them to currently used agents for brain SPECT.
• Biodistribution study in mice:
Using male Albino Swiss mice weighting 20-30 gm. Same activity were injected intravenously through their tail vein and intranasally through their nostrils.
The obtained results showed that:
• For 125I-TZ
Biodistribution study of 125I-TZ showed that IN microemulsion was much higher than IN solution and IV solution. The brain uptake of IV solution injection was 2.4 ± 0.2 %, for IN solution was 4.3±1.4 % and for INME was 6.7±0.5 % at 15 mins. Brain/Blood ratio of INME was 2.4 at 15 minutes which was the highest ratio; almost all Brain/Blood ratios did not show a significant difference from each other at microemulsion.
• For 125I-HP
Biodistribution study revealed that at 15 min post injection, brain uptake of IN microemulsion was of highest value comparable with IN solution and IV solution that was 5.7±0.4 % for INME while IN solution showed a brain uptake of 4.3±0.2 %, IV solution was 1.4±0.2 %. The Brain/Blood ratio of INME was 0.9 which is much higher than IN solution and IV solution at the same time.
• For 99mTc-PB
Biodistribution study was done using only IV solution and IN solution. IN solution showed higher brain uptake that was 4.7±0.2 % within 15 mins where the brain uptake at 15 min using IV injection was about 1.5 ±0.1 % .The Brain/Blood ratio of IN solution was also higher at 15 min post injection that was 3.4 comparable with 0.06 at same time using IV injection.