- The rate of dopaminergic loss in PD is significantly greater than that of healthy controls, and [123I]beta-CIT SPECT imaging provides a quantitative biomarker for the progressive nigrostriatal dopaminergic degeneration in PD. As new protective and restorative therapies for PD are developed, dopamine transporter imaging offers the potential to provide an objective endpoint for these therapeutic trials.

The biodistribution of radioactivity after the administration of a new tracer for alpha4beta2 nicotinic acetylcholine receptors (nAChRs), [123I]5-iodo-3-[2(S)-2-azetidinylmethoxy]pyridine (5-I-A-85380), was studied in ten healthy human subjects. Following administration of 98+/-6 MBq [123I]5-I-A-85380, serial whole-body images were acquired over 24 h and corrected for attenuation. One to four brain single-photon emission tomography (SPET) images were also acquired between 2.5 and 24 h. Estimates of radiation absorbed dose were calculated using MIRDOSE 3.1 with a dynamic bladder model and a dynamic gastrointestinal tract model. The estimates of the highest absorbed dose (microGy/MBq) were for the urinary bladder wall (71 and 140), lower large intestine wall (70 and 72), and upper large intestine wall (63 and 64), with 2.4-h and 4.8-h urine voiding intervals, respectively. The whole brain activity at the time of the initial whole-body imaging at 14 min was 5.0% of the injected dose. Consistent with the known distribution of alpha4beta2 nAChRs, SPET images showed the highest activity in the thalamus. These results suggest that [123I]5-I-A-85380 is a promising SPET agent to image alpha4beta2 nAChRs in humans, with acceptable dosimetry and high brain uptake.

Reliable quantitative dopamine transporter imaging is critical for early and accurate diagnosis of Parkinson's disease (PD). Image quantitation is made difficult by the variability introduced by manual interventions during the quantitative processing steps. A fully automated objective striatal analysis (OSA) program was applied to dopamine transporter images acquired from PD subjects with early symptoms of suspected parkinsonism and compared with manual analysis by a trained image-processing technologist. Methods: A total of 101 123 I-b-CIT SPECT scans were obtained of subjects recruited to participate in the Query-PD Study. Data were reconstructed and then analyzed according to a package of scripts (OSA) that reorients the SPECT brain volume to the standard geometry of an average scan, automatically locates the striata and occipital structures, locates the caudate and putamen, and calculates the background-subtracted striatal uptake ratio (V3$). The striatal uptake ratio calculated by OSA was compared with manual analysis by a trained image-processing technologist. Several parameters were varied in the automated analysis, including the number of summed transverse slices and the size and separation of the regions of interest applied to the caudate and putamen to determine the optimum OSA analysis. The parameters giving V3$ with the closest correlation to the manual analysis were accepted as optimal. Results: The optimal comparison between the V3$ obtained by the human analyst and that obtained by the automated OSA analysis yielded a correlation coefficient of 0.96. Conclusion: Our optimized OSA delivers V3$ evaluations that closely correlate with a similar evaluation manually applied by a highly trained image-processing technologist.

A series of reboxetine analogs was synthesized and evaluated for in vitro binding as racemic mixtures. The best candidate (INER) was synthesized as the optically pure (S,S) enantiomer, labeled with iodine-123 and its in vivo binding determined by SPECT imaging in baboons. The in vivo specificity, selectivity and kinetics of [ 123 I]INER make it a promising agent for imaging NET in vivo by noninvasive SPECT imaging.The norepinephrine transporter (NET) is a protein with twelve transmembrane-spanning domains, located at the pre-synaptic terminal of noradrenergic neurons. The principal physiological function of NET is to removes excess norepinephrine (NE) from the synaptic cleft to terminate the action of NE (avoiding over-stimulation) and to recycle NE into the presynaptic neuron (active reuptake) for later re-release. Brain structures known to be rich in NET include the locus coerulus, (brainstem area); thalamus, hippocampus and throughout the cerebral cortex, whereas low densities are found in cerebellum and striatum. 4 NET has been implicated in the pathophysiology of numerous neuropsychiatric and neurodegenerative disorders, including depression (reduced level of NE in the synapse appears to down-regulate the level of NET), 5,6 arousal, 7 anxiety, 8,9 attention-deficit/hyperactivity disorder (atomoxetine 1 is the first non-stimulant selective NET inhibitor for the treatment of ADHD 10 ), 11 and Alzheimer's disease. 12 Therefore, the development of a specific radioligand to quantify the variation of NET density in vivo will be of great utility as a diagnostic tool to better understand the etiology and pathogenesis of these neuropsychiatric disorders, as well as a tool to evaluated potential new drugs targeting the NET.

Further analyses are needed to determine which parameters are related to and possibly predictive of increased carcinoma risk.