Striatal dopamine d2/d3 receptor availability is reduced in methamphetamine dependence and is linked to impulsivity.

While methamphetamine addiction has been associated with both impulsivity and striatal dopamine D(2)/D(3) receptor deficits, human studies have not directly linked the latter two entities. We therefore compared methamphetamine-dependent and healthy control subjects using the Barratt Impulsiveness Scale (version 11, BIS-11) and positron emission tomography with [(18)F]fallypride to measure striatal dopamine D(2)/D(3) receptor availability. The methamphetamine-dependent subjects reported recent use of the drug 3.3 g per week, and a history of using methamphetamine, on average, for 12.5 years. They had higher scores than healthy control subjects on all BIS-11 impulsiveness subscales (p < 0.001). Volume-of-interest analysis found lower striatal D(2)/D(3) receptor availability in methamphetamine-dependent than in healthy control subjects (p < 0.01) and a negative relationship between impulsiveness and striatal D(2)/D(3) receptor availability in the caudate nucleus and nucleus accumbens that reached statistical significance in methamphetamine-dependent subjects. Combining data from both groups, voxelwise analysis indicated that impulsiveness was related to D(2)/D(3) receptor availability in left caudate nucleus and right lateral putamen/claustrum (p < 0.05, determined by threshold-free cluster enhancement). In separate group analyses, correlations involving the head and body of the caudate and the putamen of methamphetamine-dependent subjects and the lateral putamen/claustrum of control subjects were observed at a weaker threshold (p < 0.12 corrected). The findings suggest that low striatal D(2)/D(3) receptor availability may mediate impulsive temperament and thereby influence addiction.

Exercise elevates dopamine D2 receptor in a mouse model of Parkinson's disease: in vivo imaging with [¹8F]fallypride.

The purpose of the current study was to examine changes in dopamine D2 receptor (DA-D2R) expression within the basal ganglia of MPTP mice subjected to intensive treadmill exercise. Using Western immunoblotting analysis of synaptoneurosomes and in vivo positron emission tomography (PET) imaging employing the DA-D2R specific ligand [¹8F]fallypride, we found that high intensity treadmill exercise led to an increase in striatal DA-D2R expression that was most pronounced in MPTP compared to saline treated mice. Exercise-induced changes in the DA-D2R in the dopamine-depleted basal ganglia are consistent with the potential role of this receptor in modulating medium spiny neurons (MSNs) function and behavioral recovery. Importantly, findings from this study support the rationale for using PET imaging with [¹8F]fallypride to examine DA-D2R changes in individuals with Parkinson's Disease (PD) undergoing high-intensity treadmill training.

Enhancing neuroplasticity in the basal ganglia: the role of exercise in Parkinson's disease.

Epidemiological and clinical trials have suggested that exercise is beneficial for patients with Parkinson's disease (PD). However, the underlying mechanisms and potential for disease modification are currently unknown. This review presents current findings from our laboratories in patients with PD and animal models. The data indicate that alterations in both dopaminergic and glutamatergic neurotransmission, induced by activity-dependent (exercise) processes, may mitigate the cortically driven hyper-excitability in the basal ganglia normally observed in the parkinsonian state. These insights have potential to identify novel therapeutic treatments capable of reversing or delaying disease progression in PD.

Phase I evaluation of J591 as a vascular targeting agent in progressive solid tumors.

PURPOSE: The antibody J591 targets the external domain of prostate-specific membrane antigen, which is expressed in the neovasculature of nonprostate solid tumors. This phase I trial tested the hypothesis that J591 could be used as a vascular targeting platform for patients with nonprostate solid tumors. EXPERIMENTAL DESIGN: Patients with progressive solid tumors were eligible. Twenty patients, divided into six dosage cohorts of 3 to 6 patients each, were treated every 3 weeks to a maximum of four doses using either 5, 10, 20, 40, 60, or 100 mg of J591 antibody. Two milligrams of antibody were labeled with 10 mCi of indium-111. RESULTS: Patients with a wide variety of solid tumors were tested; all had good tumor localization. No dose-limiting toxicities were observed. The serum clearance rate decreased with increasing antibody mass, likely a result of early hepatic uptake of antibody. Half-life for each successive cohort was 0.71, 0.84, 1.86, 1.83, 3.32, and 3.56 days. Hepatic saturation seemed to occur by 60 mg. Seventeen of 18 (94%) patients with soft tissue disease on standard scans showed uptake in the soft tissues on antibody scans as did 6 of 6 patients with bone disease. CONCLUSIONS: The tumoral neovasculature of a variety of solid tumors can be selectively and safely targeted using J591. In planning for future studies using J591 as a radiation delivery platform, an antibody mass of 60 mg should be considered, as it would seem to minimize the radiation delivered to the liver while minimizing the radiation dose to bone.

Pilot trial of unlabeled and indium-111-labeled anti-prostate-specific membrane antigen antibody J591 for castrate metastatic prostate cancer.

BACKGROUND: Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein primarily expressed on benign and malignant prostatic epithelial cells. J591 is an IgG1 monoclonal antibody that targets the external domain of the PSMA. The relationship among dose, safety, pharmacokinetics, and antibody-dependent cellular cytotoxicity (ADCC) activation for unlabeled J591 has not been explored. PATIENTS AND METHODS: Patients with progressive metastatic prostate cancer despite androgen deprivation were eligible. Each patient received 10, 25, 50, and 100 mg of J591. Two milligrams of antibody, conjugated with the chelate 1,4,7,10-tetraazacyclododecane-N, N',N'',N'''-tetraacetic acid, were labeled with 5 mCi indium-111 (111In) as a tracer. One group of patients received unlabeled J591 before the labeled antibody; the other received both together. Toxicities, pharmacokinetic properties, biodistribution, ADCC induction, immunogenicity, and clinical antitumor effects were assessed. RESULTS: Fourteen patients were treated (seven in each group). Treatment was well tolerated. Biodistribution of 111In-labeled J591 was comparable in both groups. The mean T1/2 was .96, 1.9, 2.75, and 3.47 days for the 10, 25, 50, and 100 mg doses, respectively. Selective targeting of 111In-labeled J591 to tumor was seen. Hepatic saturation occurred by the 25-mg dose. ADCC activity was proportional to dose. One patient showed a >50% prostate-specific antigen decline. CONCLUSIONS: J591 is well tolerated in repetitive dose-escalating administrations. The rate of serum clearance decreases with increasing antibody mass. ADCC activation is proportional to antibody mass. The optimal dose is 25 mg for radioimmunotherapy and 100 mg for immunotherapy. Phase II studies using J591 as a radioconjugate are under way.

Treadmill exercise elevates striatal dopamine D2 receptor binding potential in patients with early Parkinson's disease.

We have previously demonstrated changes in dopaminergic neurotransmission after intensive exercise in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mouse model of Parkinson's disease (PD), including an increase in the dopamine D2 receptor (DA-D2R), using noninvasive PET imaging with the radioligand [18F]fallypride. The purpose of this feasibility and translational study was to examine whether intensive exercise leads to similar alterations in DA-D2R expression using PET imaging with [18F]fallypride in individuals with early-stage PD. In this pilot study, four patients with early-stage PD were randomized to receive intensive exercise (treadmill training sessions three times/week for 8 weeks) or no exercise. Two healthy age-matched individuals participated in treadmill training. Alterations in the DA-D2R binding potential (BP) as a marker for receptor expression were determined using PET imaging with [18F]fallypride. Turning performance in the patients with PD as a measure of postural control and the Unified Parkinson's Disease Rating Scale scores pre-exercise and postexercise were determined. Our data showed an exercise-induced increase in [18F]fallypride BP as well as improved postural control in patients with PD who exercised. Changes in DA-D2R BP were not observed in patients with PD who did not exercise. These results suggest that exercise can lead to neuroplasticity in dopaminergic signaling and contribute to improved function that may be task specific (postural control) in early-stage PD.