Contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI) are routinely used to diagnose soft tissue and vascular abnormalities. However safety concerns limit the use of iodinated and gadolinium- (Gd) based CT and MRI contrast media in renally compromised patients. With an estimated 14% of the US population suffering from chronic kidney disease (CKD), contrast media compatible with renal impairment is sorely needed. We present the new manganese(II) complex [Mn(PyC3A)(H2O)]- as a Gd alternative. [Mn(PyC3A)(H2O)]- is amongst the most stable Mn(II) complexes at pH 7.4 (log KML = 11.40). In the presence of 25 mol equiv. Zn at pH 6.0, 37 °C, [Mn(PyC3A)(H2O)]- is 20-fold more resistant to dissociation than [Gd(DTPA)(H2O)]2-. Relaxivity of [Mn(PyC3A)(H2O)]- in blood plasma is comparable to commercial Gd contrast agents. Biodistribution analysis confirms that [Mn(PyC3A)(H2O)]- clears via a mixed renal/ hepatobiliary pathway with >99% elimination by 24h. [Mn(PyC3A)(H2O)]- was modified to form a bifunctional chelator and 4 chelates were conjugated to a fibrin-specific peptide to give Mn-FBP. Mn-FBP binds the soluble fibrin fragment DD(E) with Kd = 110 nM. Per Mn relaxivity of Mn-FBP is 4-fold greater than [Mn(PyC3A)(H2O)]- and increases 60% in the presence of fibrin, consistent with binding. Mn-FBP provided equivalent thrombus enhancement to the state of the art Gd analog, EP-2104R, in a rat model of arterial thrombosis. Mn metabolite analysis reveals no evidence of dechelation and the probe was >99% eliminated after 24 hr. [Mn(PyC3A)(H2O)]- is a lead development candidate for an imaging probe that is compatible with renally compromised patients.

Background: There is significant evidence for cognitive decline following deep brain stimulation (DBS). Current stimulation paradigms utilize gamma frequency stimulation for optimal motor benefits; however, little has been done to optimize stimulation parameters for cognition. Recent evidence implicates subthalamic nucleus (STN) theta oscillations in executive function, and theta oscillations are well-known to relate to episodic memory, suggesting that theta frequency stimulation could potentially improve cognition in Parkinson's disease (PD). Objective: To evaluate the acute effects of theta frequency bilateral STN stimulation on executive function in PD versus gamma frequency and off, as well as investigate the differential effects on episodic versus nonepisodic verbal fluency. Methods: Twelve patients (all males, mean age 60.8) with bilateral STN DBS for PD underwent a doubleblinded, randomized cognitive testing during stimulation at (1) 130e135 Hz (gamma), (2) 10 Hz (theta) and (3) off. Executive functions and processing speed were evaluated using verbal fluency tasks (letter, episodic category, nonepisodic category, and category switching), color-word interference task, and random number generation task. Performance at each stimulation frequency was compared within subjects. Results: Theta frequency significantly improved episodic category fluency compared to gamma, but not compared to off. There were no significant differences between stimulation frequencies in other tests. Conclusion:In this pilot trial, our results corroborate the role of theta oscillations in episodic retrieval, although it is unclear whether this reflects direct modulation of the medial temporal lobe and whether similar effects can be found with more canonical memory paradigms. Further work is necessary to corroborate our findings and investigate the possibility of interleaving theta and gamma frequency stimulation for concomitant motor and cognitive effects.