Uta Funke , Winnie Deuther-Conrad , Gregor Schwan , Aurélie Maisonial , Matthias Scheunemann , Steffen Fischer , Achim Hiller , Detlef Briel and Peter Brust
Article: Radiosynthesis and Radiotracer Properties of a 7-(2-[¹⁸F]Fluoroethoxy)-6-methoxypyrrolidinylquinazoline for Imaging of Phosphodiesterase 10A with PET
Pharmaceuticals 2012, 5(2), 169-188; doi:10.3390/ph5020169 - published online 6 February 2012
Show/Hide AbstractAbstract: Phosphodiesterase 10A (PDE10A) is a key enzyme of intracellular signal transduction which is involved in the regulation of neurotransmission. The molecular imaging of PDE10A by PET is expected to allow a better understanding of physiological and pathological processes related to PDE10A expression and function in the brain. The aim of this study was to develop a new ¹⁸F-labeled PDE10A ligand based on a 6,7-dimethoxy-4-pyrrolidinylquinazoline and to evaluate its properties in biodistribution studies. Nucleophilic substitution of the 7-tosyloxy-analogue led to the 7-[¹⁸F]fluoroethoxy-derivative [¹⁸F]IV with radiochemical yields of 25% ± 9% (n = 9), high radiochemical purity of ≥99% and specific activities of 110–1,100 GBq/μmol. [¹⁸F]IV showed moderate PDE10A affinity (K_D,PDE10A = 14 nM) and high metabolic stability in the brain of female CD-1 mice, wherein the radioligand entered rapidly with a peak uptake of 2.3% ID/g in striatum at 5 min p.i. However, ex vivo autoradiographic and in vivo blocking studies revealed no target specific accumulation and demonstrated [¹⁸F]IV to be inapplicable for imaging PDE10A with PET.

Claudia Stöllberger and Josef Finsterer
Review: Concerns Regarding the Use of Dabigatran for Stroke Prevention in Atrial Fibrillation
Pharmaceuticals 2012, 5(2), 155-168; doi:10.3390/ph5020155 - published online 3 February 2012
Show/Hide AbstractAbstract: Dabigatran is an oral thrombin inhibitor which has been approved in several countries as an alternative to vitamin-K-antagonists for the prevention of stroke or embolism in atrial fibrillation patients. Dabigatran is introduced into clinical practice, although many issues regarding this drug are still unclear, like laboratory monitoring, use in elderly patients, drug- and food-interactions and use in patients with renal insufficiency. Additionally, there is no antidote for dabigatran. Thus, aim of the present review is to give an overview of concerns and unresolved issues concerning dabigatran.

Noriaki Kawano , Fumiyuki Kiuchi , Nobuo Kawahara and Kayo Yoshimatsu
Article: Genetic and Phenotypic Analyses of a Papaver somniferum T-DNA Insertional Mutant with Altered Alkaloid Composition
Pharmaceuticals 2012, 5(2), 133-154; doi:10.3390/ph5020133 - published online 2 February 2012
Show/Hide AbstractAbstract: The in vitro shoot culture of a T-DNA insertional mutant of Papaver somniferum L. established by the infection of Agrobacterium rhizogenes MAFF03-01724 accumulated thebaine instead of morphine as a major opium alkaloid. To develop a non-narcotic opium poppy and to gain insight into its genetic background, we have transplanted this mutant to soil, and analyzed its alkaloid content along with the manner of inheritance of T-DNA insertion loci among its selfed progenies. In the transplanted T₀ primary mutant, the opium (latex) was found to be rich in thebaine (16.3% of dried opium) by HPLC analysis. The analyses on T-DNA insertion loci by inverse PCR, adaptor-ligation PCR, and quantitative real-time PCR revealed that as many as 18 copies of T-DNAs were integrated into a poppy genome in a highly complicated manner. The number of copies of T-DNAs was decreased to seven in the selected T₃ progenies, in which the average thebaine content was 2.4-fold that of the wild type plant. This may indicate that the high thebaine phenotype was increasingly stabilized as the number of T-DNA copies was decreased. In addition, by reverse transcription PCR analysis on selected morphine biosynthetic genes, the expression of codeine 6-O-demethylase was clearly shown to be diminished in the T₀ in vitro shoot culture, which can be considered as one of the key factors of altered alkaloid composition.

Michael R. Brandt , Chad E. Beyer and Stephen M. Stahl
Review: TRPV1 Antagonists and Chronic Pain: Beyond Thermal Perception
Pharmaceuticals 2012, 5(2), 114-132; doi:10.3390/ph5020114 - published online 2 February 2012
Show/Hide AbstractAbstract: In the last decade, considerable evidence as accumulated to support the development of Transient Receptor Potential Vanilloid 1 (TRPV1) antagonists for the treatment of various chronic pain conditions. Whereas there is a widely accepted rationale for the development of TRPV1 antagonists for the treatment of various inflammatory pain conditions, their development for indications of chronic pain, where conditions of tactical, mechanical and spontaneous pain predominate, is less clear. Preclinical localization and expression studies provide a firm foundation for the use of molecules targeting TRPV1 for conditions of bone pain, osteoarthritis and neuropathic pain. Selective TRPV1 antagonists weakly attenuate tactile and mechanical hypersensivity and are partially effective for behavioral and electrophysiological endpoints that incorporate aspects of spontaneous pain. While initial studies with TRPV1 antagonist in normal human subjects indicate a loss of warm thermal perception, clinical studies assessing allelic variants suggests that TRPV1 may mediate other sensory modalities under certain conditions. The focus of this review is to summarize the current perspectives of TRPV1 for the treatment of conditions beyond those with a primary thermal sensitivity.

Victor V. Levenson and Anatoliy A. Melnikov
Review: DNA Methylation as Clinically Useful Biomarkers—Light at the End of the Tunnel
Pharmaceuticals 2012, 5(1), 94-113; doi:10.3390/ph5010094 - published online 18 January 2012
Show/Hide AbstractAbstract: A recent expansion of our knowledge about epigenetic changes strongly suggests that epigenetic rather than genetic features better reflect disease development, and consequently, can become more conclusive biomarkers for the detection and diagnosis of different diseases. In this paper we will concentrate on the current advances in DNA methylation studies that demonstrate a direct link between abnormal DNA methylation and a disease. This link can be used to develop diagnostic biomarkers that will precisely identify a particular disease. It also appears that disease-specific DNA methylation patterns undergo unique changes in response to treatment with a particular drug, thus raising the possibility of DNA methylation-based biomarkers for the monitoring of treatment efficacy, for prediction of response to treatment, and for the prognosis of outcome. While biomarkers for oncology are the most obvious applications, other fields of medicine are likely to benefit as well. This potential is demonstrated by DNA methylation-based biomarkers for neurological and psychiatric diseases. A special requirement for a biomarker is the possibility of longitudinal testing. In this regard cell-free circulating DNA from blood is especially interesting because it carries methylation markers specific for a particular disease. Although only a few DNA methylation-based biomarkers have attained clinical relevance, the ongoing efforts to decipher disease-specific methylation patterns are likely to produce additional biomarkers for detection, diagnosis, and monitoring of different diseases in the near future.

Albert J. Chang , Ravindra DeSilva , Sandeep Jain , Kimberley Lears , Buck Rogers and Suzanne Lapi
Article: ⁸⁹Zr-Radiolabeled Trastuzumab Imaging in Orthotopic and Metastatic Breast Tumors
Pharmaceuticals 2012, 5(1), 79-93; doi:10.3390/ph5010079 - published online 5 January 2012
Show/Hide AbstractAbstract: The human epidermal growth factor receptor 2 (HER2/neu) is overexpressed in 20–30% of breast cancers and is associated with tumor growth, angiogenesis, and development of distant metastases. Trastuzumab, an anti-HER2 monoclonal antibody, is used for the treatment of HER2 positive breast cancer and clinical efficacy of this agent is dependent on HER2 expression. Targeted PET imaging of HER2 with radiolabeled trastuzumab may be used to determine HER2 expression levels and guide therapy selection. The purpose of the current study was to evaluate a facile ⁸⁹Zr-trastuzumab preparation method that can be efficiently applied for clinical grade production. Also, relative HER2 expression levels in orthotopic and metastatic breast cancer models were assessed by PET imaging using the ⁸⁹Zr-trastuzumab produced by this simpler method.