(7)3,4-Methylenedioxymethamphetamine (MDMA, 'Ecstasy') is a widely used illicit drug that produces toxic effects on brain serotonin axons and axon terminals in animals. The results of clinical studies addressing MDMA's serotonin neurotoxic potential in humans have been inconclusive. In the present study, 23 abstinent MDMA users and 19 non-MDMA controls underwent quantitative positron emission tomography (PET) studies using [ 11 C]McN5652 and [ 11 C]DASB, first-and second-generation serotonin transporter (SERT) ligands previously validated in baboons for detecting MDMA-induced brain serotonin neurotoxicity. Global and regional distribution volumes (DVs) and two additional SERT-binding parameters (DV spec and DVR) were compared in the two subject populations using parametric statistical analyses. Data from PET studies revealed excellent correlations between the various binding parameters of [ 11 C] McN5652 and [ 11 C]DASB, both in individual brain regions and individual subjects. Global SERT reductions were found in MDMA users with both PET ligands, using all three of the above-mentioned SERT-binding parameters. Preplanned comparisons in 15 regions of interest demonstrated reductions in selected cortical and subcortical structures. Exploratory correlational analyses suggested that SERT measures recover with time, and that loss of the SERT is directly associated with MDMA use intensity. These quantitative PET data, obtained using validated first-and second-generation SERT PET ligands, provide strong evidence of reduced SERT density in some recreational MDMA users.

Abstract-The angiotensin II subtype 1 receptor (AT 1 R) has been linked to the development and progression of renovascular hypertension. In this study we applied a pig model of renovascular hypertension to investigate the AT 1 R in vivo with positron-emission tomography (PET) and in vitro with quantitative autoradiography. AT 1 R PET measurements were performed with the radioligand [ 11 C]KR31173 in 11 control pigs and in 13 pigs with hemodynamically significant renal artery stenosis; 4 were treated with lisinopril for 2 weeks before PET imaging. The radioligand impulse response function was calculated by deconvolution analysis of the renal time-activity curves. Key Words: positron-emission tomography Ⅲ angiotensin AT 1 receptor Ⅲ swine Ⅲ animal models Ⅲ renovascular hypertension R enovascular hypertension is the most common type of secondary hypertension that occurs in 2 to 4 million people in the United States. The renin-angiotensin system and its component, the angiotensin II subtype 1 receptor (AT 1 R), have been tightly linked to the development and progression of renovascular hypertension (RVH), but experimental mechanistic evidence for regulation of the AT 1 R has not been established in vivo. Antagonists against the angiotensin-converting enzyme (ACE; ACE inhibitors) or the AT 1 R (angiotensin receptor blockers) continue to play a key role in the therapy of renal hypertension and other kidney diseases. 1 Both drugs represent a "doubleedged sword," because they may deactivate regulatory effects of the renin-angiotensin system and the AT 1 R and trigger irreversible renal damage. 2 The complexity of the management of RVH raises a pressing need for an in vivo imaging technique that cannot only demonstrate reduced blood flow to the organ but also detect and monitor renal ischemia at the molecular level. [3][4][5][6] Magnetic resonance (MR) angiography (MRA) and computed tomography angiography are oriented toward depicting anatomy rather than tissue injury. 7,8 Radionuclide captopril renography has not been widely accepted 9 because of its limited accuracy in the presence of bilateral disease 10 or therapy with ACE inhibitors. 11 Inhibiting the activity of the AT 1 R with angiotensin receptor blockers or ACE inhibitors, on the other hand, is widely adapted by clinicians to protect the kidney from renal injury. [12][13][14][15][16] Probing molecular changes is expected to assist diagnosis and support prediction and evaluation of treatment success. We have identified the AT 1 R as a significant molecular imaging target because of its intricate involvement in the many aspects of renal physiology and pathology, [17][18][19] particularly in acute, subacute, and chronic complications of renal ischemia. 20,21 The AT 1 R is a key injury response protein because its continuing activation leads to stimulation of the extracellular matrix, 22 collagen deposition, glomerular remodeling, 23 inflammation, 24 apoptosis, 25 generation of oxygen species, and cell cycle arrest. 26 To this end, our group has synthesized several ...

The goal of this study was to investigate the binding characteristics of [ 11 C]KR31173 and its applicability for PET studies of the AT 1 receptor (AT 1 R). Methods-Exvivo biodistribution and pharmacology were tested in mice. PET imaging was performed in mice, beagle dogs, and a baboon. To assess nonspecific binding, PET imaging was performed both before and after pretreatment with a potent AT 1 R antagonist. In the baboon, PET imaging was also performed with the previously developed radioligand [ 11 C]L-159,884 for comparison.Results-Ex vivo biodistribution studies in mice showed specific binding rates of 80-90% in the adrenals, kidneys, lungs, and heart. Specific binding was confirmed in mice using small animal PET. In dogs, renal cortex tissue concentration at 75-95 min post-injection was 63 nCi/mL/mCi at a specific binding rate of 95%. In the baboon renal cortex, tissue activity at 55-75 min post injection was 345 nCi/mL/mCi. The specific binding of [ 11 C]KR31173 was higher (81%) in the baboon than the specific binding of [ 11 C]L-159,884 (34%). Conclusion-[11 C]KR31173 shows accumulation and significant specific binding to the AT 1 R in the kidneys of mice, dogs, and baboon. These findings suggest that this radioligand is suited for imaging the renal cortical AT 1 R in multiple species.

This study reveals, for the first time, that chronic ACEI treatment increases AT(1)R binding in vivo in the dog renal cortex.