C-11-Choline
Methyl Choline labeled with C-11 (C-11-MC) is a promising new agent for tumor imaging using PET. Evidence suggests increased synthesis of membrane phosphatidylcholine in tumor cells that is correlated with high uptake of this radiopharmaceutical in malignant tissue. In contrast to F-18 -fluorodeoxyglucose (FDG), its uptake into benign structures such as the normal brain, heart and urinary tract is negligible, resulting in a higher target to background signal ratio in tumors located near those benign structures. Another advantage of C-11-MC is its rapid disappearance from the blood pool, within minutes, while the plateau of F-18-FDG uptake into tumors may be reached only after hours.
Therefore the diagnostic content of C-11-MC images is already stable after 5-15 minutes. Our aim was to evaluate the usefulness of PET imaging with C-11-MC for the diagnosis, staging and therapy follow up of malignant tumors. An automated synthetic route to C-11-MC was developed in our lab including QC procedure. Human studies with [C-11] Choline-PET were started in patients suffering of brain or prostatic tumor.
C-11 - Deprenyl and Parkinson's Disease
One field of interest in the area of PET neurology is the monoamine oxidase system. Unlike most enzymes, neurotransmitters and transporters, MAO B increases with normal aging and in neurodegenerative diseases. MAO B is implicated in the neurodegenerative mechanism which occurs in Parkinson's disease.
A major milestone in the study of MAO B has been the design and synthesis of the highly selective inhibitor L-deprenyl which irreversibly inhibits MAO B by binding covalently to the enzyme itself. In the last decade, L-deprenyl has been labeled with the short-lived radioisotope carbon-11 (half- life 20 min.).
Simultaneous spatial and temporal measurement of the concentration of the tracer in the living human body is possible with the non-invasive PET technique. By this method, C-11-L-deprenyl was used for directly mapping the distribution and function of MAO B in the human brain. Our objectives are to develop the PET methodology further to evaluate the pharmacokinetics in normal human subjects of a new MAO B inhibitor which is a potentially superior anti-Parkinson drug: TVP-1012 made by Teva company, using C-11-deprenyl. A baseline measurement of a single PET scan was performed on each of 3 young healthy normal volunteers (age range: 20-30 years) after injection of 7.5 mCi C-11-L-deprenyl
Epidermal Growth Factor Receptor and PET
Epidermal growth factor receptor-tyrosine kinase (EGFR-TK) is over-expressed in a large number of human cancers. Novel PET tracers for EGFR-TK will allow for the measurement of the level of expression of these macromolecules in vivo in cancer.
Such data will enable better decisions in regard to patient therapeutic course of action, and open up research opportunities in cancer research and in anticancer drug development. In our search for F-18-labeled EGFR-TK PET tracers, we have prepared five new compounds. These compounds were evaluated in vitro and in vivo. PET study of the leading tracer was performed on tumor bearing nude mice.
A new generation of irreversible EGFR-TK inhibitors PET tracers are currently under study.
Dopamine and PET
Nowadays, [F-18] F-DOPA has become an important tracer to study the presynaptic dopamine metabolism in vivo with PET. We were prompted to produce [F-18]F-DOPA for a study combining electrophysiological records and PET imaging in order to understand the tremor phenomena in Parkinson's patients and in primates treated with MPTP.
We will also use [F-18]F-DOPA in patients: psychophysical tests and PET imaging of the basal ganglia (with decrease of [F-18] F-DOPA uptake) might help to diagnose PD before the appearance of symptoms.
In order to achieve this goal, a semi-automated one-pot radiosynthesis of [F-18] F-DOPA was developed in our facility. This simple and reliable automated procedure was routinely used in our laboratory in the last six months. [F-18] F-DOPA was produced with a 20% yield and high chemical and radiochemical purity. [F-18] F-DOPA was used in a monkey experiment to create an image of the basal ganglia. Time activity curve was successfully drawn for this brain region.
Final approval of the Helsinki Committee for Human Studies was obtained and we started the above research project and performed a baseline study of F-18-FDOPA in normal volunteers.
(0-15) Water PE - Sexual arousal and Cerebral blood flow
PET and 15O-H2O were used to measure changes in regional cerebral blood flow (rCBF) during sexual arousal evoked in 10 young heterosexual males while they watched a pornographic video clip, featuring heterosexual intercourse.
This condition was compared with other mental setups evoked by noisy, nature and talkshow audiovisual clips. Immediately after each clip, the participants answered three questions pertaining to what extent they thought about sex, felt aroused and sensed an erection. They scored their answers using a 1 to10 scale. SPM was used for data analysis.
Sexual arousal was mainly associated with activation of bilateral, predominantly right, inferoposterior visual extrastriate cortices, of the right inferolateral prefrontal cortex and of the midbrain. The right inferolateral prefrontal cortex activation can be related to two facets of cognition ("mind-reading" and "mirroring") that may be present in the sexual arousal provoked by the video clip.
The midbrain activation may be related to the dopaminergic mesolimbic system or to the connections of the limbic system and the hypothalamus with the autonomous nervous system in the periaqueductal gray matter.
PET/Cyclotron Related Grants
1. Grant of Neural Computational Center of the Hebrew University (1997) (26,500 $): Imaging of Brain Activity in the Cortex of Awake Monkeys Using PET-15O and MRI. Atlan, H., Chisin, R., Amit, D., Hochstein, S., Vaadia, E.
2. Grant of the Israeli Ministry of Health (1997) (30,000 NIS): Combined Electrophysiological and PET Evaluation of the Tremor Phenomena in Patients with Parkinson’s Disease and MPTP-Treated Monkeys. Aharon, I., Chisin, R., Berman, H., Reches, A., Krausz, Y., Gomori, J. M., Madar, I. (Chisin, R., Principal Investigator).
3. Grant of TEVA Pharmaceutical Company (1998) (89,525 $): A new MAO B inhibitor anti-Parkinson drug. Mishani, E., Freedman, N., Rubinstein, R., Krausz, Y., and Chisin, R. (Mishani, E., Principal Investigator Part I; Chisin, R., Principal Investigator Part II: PET brain studies).
4. Grant of the Binational Science Foundation (1999-2002) (114,000 $): Labeled PET tracers for EGFr-TK and estrogen receptors. Mishani, E. (PI), Collaboration with Prof. A. Levitzky, # 17, 20, 21, 22, 25, 27, 28. # abstracts 9, 10.
5. Grant of the International Atomic Energy Agency (1999: 47,230$; 2000: 108,015 : National and Regional Production of Fluorinated Radiopharmaceuticals - Clinical and Scientific Aspects. Chisin, R., Mishani, E.
6. Grant of the Israeli Ministry of Health (2000) (30,000 NIS): Unilateral spatial neglect and awareness of deficits: A longitudinal study using PET imaging and conventional and functional measures. Katz, N., Bocher, M., Freedman, N., Biran, I., BarHaim, A., Chisin, R., and Abramsky, O.
7. Creation of a start-up company on EFGR, Hadassah-Hebrew University – Naiot (Collaboration with Prof. A. Levitzky) (2001).
8. Grant of the Israel Cancer Association (2001) (40,000 NIS): Evaluation of prostate cancer patients with PET using C-11-choline. Bocher, M., Mishani, E., Pode, D., Chisin, R.
9. Grant of NIH (2003) (237,000 $/year for 4 years): Functional dopamine neurons from human ES cells. Reubinoff, B.E. (PI), Ben Hur, T. (CI), Bergman, H. (CI), Mishani, E. (CI), Segal, M. (CI). |