The dopamine transporter is expressed almost exclusively on dopamine neurons and is an effective marker for the neurons. The transporter has been imaged in Parkinson's disease and other neurological diseases to determine the condition of dopamine neurons. The status of the dopamine transporter is also under investigation as the protein is a principal target of cocaine and methylphenidate (or Ritalin, a drug therapy for Attention Deficit Hyperactivity Disorder). Accordingly, imaging of the dopamine transporter in brain is one of the most rapidly growing fields of brain PET and SPECT imaging. Isotopes such as [11C] or [18F ] for PET or [123I] for SPECT imaging are generally incorporated into brain imaging probes. However, 99mtechnetium (99mTc) is widely used in imaging of peripheral tissues because it can be generated in the laboratory, obviating the need for producing [11C]) by a cyclotron or shipping [123I] long distances. However, progress in developing Tc-based probes for brain imaging has been slow because technetium chelates do not readily penetrate the brain. In our ongoing research to develop effective imaging agents for the transporter, we tested the feasibility of developing a technetium (99Tc) probe. We linked chelated rhenium to analogs of WIN 35,428, the ligands of choice for PET and SPECT imaging of the dopamine transporter. Previously, we reported the design and synthesis of a 99mTc imaging agent, technepine, that crossed the blood-brain barrier and selectively labeled dopamine-rich neurons. Technepine was the first reported technetium-labeled compound to cross the blood-brain barrier and accumulate in a selective target in brain. We are currently investigating other compounds which may increase the signal noise ratio in the brain. Using [3H]WIN 35,428 to label the dopamine transporter and [3H]citalopram to label the serotonin transporter in monkey striatum, we identified several novel rhenium analogs that are potent and selective for the transporter. O-1196 displayed high affinity (IC50 9.35 nM) and 65-fold selectivity for the dopamine over the serotonin transporter. To investigate brain penetrance of this compound, PET imaging of the dopamine transporter was conducted in adult rhesus monkeys using [11C]WIN 35,428 to label the transporter. Occupancy of the transporter by O-1196 was measured by the loss of [11C]WIN 35,428 labeled sites in the striatum. O-1196 crossed the blood-brain barrier and displaced [11C]WIN 35,428 in the striatum. This study further supports the feasibility of developing technetium-labeled compounds to image brain receptors and transporters. Research is planned to improve the synthetic steps, optimize other probes and develop methods to quantify brain images in rhesus monkeys of the technetium chelate. Madras BK, Jones AG, Mahmood A, Zimmerman RE, Holman BL, Davison A, Blundell P, Meltzer PC. Technepine A high affinity 99mtechnetium SPECT probe to label the dopamine transporter in brain, Synapse, 22:239-246, 1996. Jones AJ, Meltzer PC, Mahmood A, Zimmerman RE, Garada B, Holman BL, Davison A, Blundell P, Madras BK. Technepine a 99mtechnetium SPECT imaging agent to label the dopamine transporter in brain, Soc. Nucl. Med. Abst., 37:57, 1996. Meltzer PC, Madras BK. Imaging of dopamine transporters in humans with technetium-99m TRODAT-1. Eur. J. Nucl. Med. 24 462, 1997. Meltzer PC, Blundell P, Jones AG, Mahmood A, Garada B, Zimmerman RE, Davison A, Holman BL, Madras BK. A technetium- 99m SPECT imaging agent which targets the dopamine transporter in primate brain, J. Med. Chem., 40 1835-1844, 1997. Meltzer PC, Blundell P, Jones AG, Mahmood A, Zimmerman, RE, Garada B, Holman BL, Davison A, Madras BK. Design and synthesis of technepine the first in vivo 99mtechnetium SPECT probe which labels the dopamine transporter. NIDA Research Monograph, L. Harris
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