The prostate-specific membrane antigen (PSMA) is increasingly recognized as a viable target for imaging and therapy of cancer. We prepared seven 99mTc/Re-labeled compounds by attaching known Tc/Re chelating agents to an amino-functionalized PSMA inhibitor (lys-NHCONH-glu) with or without a variable length linker moiety. Ki values ranged from 0.17 to 199 nM. Ex vivo biodistribution and in vivo imaging demonstrated the degree of specific binding to engineered PSMA+ PC3 PIP tumors. PC3-PIP cells are derived from PC3 that have been transduced with the gene for PSMA. Despite demonstrating nearly the lowest PSMA inhibitory potency of this series, [99mTc(CO)3(L1)]+ (L1 = (2-pyridylmethyl)2N(CH2)4CH(CO2H)-NHCO-(CH2)6CO-NH-lys-NHCONH-glu) showed the highest, most selective PIP tumor uptake, at 7.9 ± 4.0% injected dose per gram of tissue at 30 min postinjection. Radioactivity cleared from nontarget tissues to produce a PIP to flu (PSMA-PC3) ratio of 44:1 at 120 min postinjection. PSMA can accommodate the steric requirements of 99mTc/Re complexes within PSMA inhibitors, the best results achieved with a linker moiety between the ε amine of the urea lysine and the chelator.

To extend our development of new imaging agents targeting the prostate-specific membrane antigen (PSMA), we have used the versatile intermediate 2-

Objectives To quantify acute myocardial retention of cardiac-derived stem cells (CDCs) and evaluate different delivery methods using Positron Emission Tomography (PET). Background Success of stem cell transplantation for cardiac regeneration is partially limited by low retention/engraftment of the delivered cells. A clinically applicable method for accurate quantification of cell retention would enable optimization of cell delivery. Methods CDCs derived from syngeneic, male Wistar Kyoto (WK) rats were labeled with 18FDG and injected intramyocardially into the ischemic region of female WK rats following permanent left coronary artery ligation. The effects of fibrin glue, bradycardia (adenosine) and cardiac arrest were examined. 18FDG PET was performed for quantification of cell retention. Quantitative PCR for the male-specific SRY gene was performed to validate the PET results. Results Myocardial retention of cells suspended in PBS 1 hr after delivery was 17.6±11.5% by PCR and 17.8±7.3% by PET. When CDCs were injected immediately following induction of cardiac arrest, retention was increased to 75.6±18.6%. Adenosine slowed the ventricular rate and doubled CDC retention (35.4±5.3%). A similar increase in CDC retention was observed following epicardial application of fibrin glue at the injection site (37.5±8.2%). PCR revealed a significant increase in 3 week cell engraftment in the fibrin glue animals (22.1±18.6% vs 5.3±3.1%, for fibrin glue and PBS respectively). Conclusions In vivo PET permits accurate measurement of CDC retention early after intramyocardial delivery. Sealing injection sites with fibrin glue or lowering ventricular rate by adenosine may be clinically translatable methods for improving stem cell engraftment in a beating heart.

Gallium-68 is a generator-produced radionuclide for positron emission tomography (PET) that is being increasingly used for radiolabeling of tumor-targeting peptides. Compounds [68Ga]3 and [68Ga]6 are high-affinity, urea-based inhibitors of the prostate-specific membrane antigen (PSMA) that were synthesized in decay-uncorrected yields ranging from 60 – 70% and radiochemical purities of more than 99%. Compound [68Ga]3 demonstrated 3.78 ± 0.90 percent injected dose per gram of tissue (%ID/g) within PSMA+ PIP tumor at 30 min post-injection, while [68Ga]6 showed a two hour PSMA+ PIP tumor uptake value of 3.29 ± 0.77%ID/g. Target (PSMA+ PIP) to non-target (PSMA− flu) ratios were 4.6 and 18.3, respectively, at those time points. Both compounds delineated tumor clearly by small animal PET. The urea series of imaging agents for PSMA can be radiolabeled with 68Ga, a cyclotron-free isotope useful for clinical PET studies, with maintenance of target specificity.

Purpose: Previously, we showed successful imaging of xenografts that express the prostatespecific membrane antigen (PSMA) using small-animal positron emission tomography (PET) and the radiolabeled PSMA inhibitor]methyl-L-cysteine. Herein, we extend that work by preparing and testing a PSMA inhibitor of the same class labeled with fluorine-18. High radiopharmaceutical uptake was also seen in kidneys and bladder; however, washout of radioactivity from these organs was faster than from the PIP tumors. The maximum PIP tumor uptake was 8.16 F 2.55% injected dose per gram, achieved at 60 min after injection, which decreased to 4.69 F 0.89 at 120 min. The PIP tumor to muscle ratio was 20 at 120 min after injection. Based on the mouse biodistribution, the dose-limiting organ is the kidneys (human estimated absorbed dose: 0.05 mGy/MBq; 0.2 rad/mCi). Conclusion: [

Objectives We examined the sodium-iodide symporter (NIS) which promotes in vivo cellular uptake of 99mTc or 124I, as a reporter gene for cell tracking by SPECT or PET imaging. Background Stem cells offer the promise of cardiac repair. Stem cell labeling is a prerequisite to tracking cell fate in vivo. Methods The human NIS cDNA was transduced into rat cardiac-derived stem cells (rCDCs) using lentiviral vectors. Rats were injected intra-myocardially with up to 4 million NIS+-rCDCs immediately following LAD ligation. Dual isotope SPECT (or PET) imaging was performed, using 99mTc (or 124I) for cell detection and 201Tl (or 13NH3) for myocardial delineation. In a subset of animals, high resolution ex vivo SPECT scans of explanted hearts were obtained to confirm that in vivo signals were derived from the cell injection site. Results NIS expression in rCDCs did not affect cell viability and proliferation. NIS activity was verified in isolated transduced cells by measuring 99mTc uptake. NIS+ rCDCs were visualized in vivo as regions of 99mTc or 124I uptake within a perfusion deficit in the SPECT and PET images, respectively. Cells could be visualized by SPECT up to day 6 post-injection. Ex vivo SPECT confirmed that in vivo 99mTc signals were localized to the cell injection sites. Conclusion Ectopic NIS expression allows non invasive in vivo stem cell tracking in the myocardium, using either SPECT or PET. The general approach shows significant promise in tracking the fate of transplanted cells participating in cardiac regeneration, given its ability to observe living cells using clinically-applicable imaging modalities.

OBJECTIVE -Clinical trials provide information regarding the safety and efficacy of medications used to manage type 2 diabetes but do not elucidate drug effectiveness in a typical managed care environment. The aim of this study was to characterize "real-world" drug utilization patterns from both a prescriber and a patient perspective.RESEARCH DESIGN AND METHODS -We conducted a retrospective analysis of a large administrative pharmacy claims database, using data on continuously pharmacy benefiteligible members prescribed oral hypoglycemic agents (OHAs).RESULTS -The 12-month persistence rate for the OHA cohort was low, ranging from 31% for ␣-glucosidase inhibitors to 60% for metformin; compliance rates varied between 70 and 80%. During the first 12 months of therapy, 36% of the patients remaining on therapy at 12 months had one or more therapy modifications. The mean number of therapy changes increased with the length of patient follow-up, with more than half of all patients experiencing at least one therapy change over the duration of follow-up.CONCLUSIONS -These findings document the wide variation in utilization patterns associated with pharmacological management of type 2 diabetes, suggesting that opportunity exists to optimize its pharmacological management.

The contributions of applied behavior analysis as a natural science approach to the study of human behavior are acknowledged. However, it is also argued that applied behavior analysis has provided limited access to the full range of environmental events that influence socially significant behavior. Recent changes in applied behavior analysis to include analysis of side effects and social validation represent ways in which the traditional applied behavior analysis conceptual and methodological model has been profitably expanded. A third area of expansion, the analysis of setting events, is proposed by the authors. The historical development of setting events as a behavior influence concept is traced. Modifications of the basic applied behavior analysis methodology and conceptual systems that seem necessary to setting event analysis are discussed and examples of descriptive and experimental setting event analyses are presented.