Editorial [Hot Topic: PET and SPECT in Drug Evaluation and Drug Design Imaging Inflammatory Processes, Tumors, and the Endocannabinoid System(Executive Editor: Aren van Waarde)]

This is the fifth issue of Current Pharmaceutical Design discussing applications of PET and SPECT in drug development. The initial issue (Vol.6, No.16, 2000) described methods for measuring the deposition, biodistribution and pharmacokinetics of drugs including their interactions with specific targets. The second issue (Vol.8, No.16, 2002) focused on the interface between nuclear medicine and molecular biology. A third issue (Vol.10, No.13, 2004) identified novel areas where molecular imaging could contribute to drug design: anti-angiogenic therapy, modulation of programmed cell death, suppression of beta-amyloid plaque formation, inhibition of cerebral acetylcholinesterase and of P-glycoprotein-mediated drug transport in the blood-brain barrier, downregulation of beta-adrenoceptors by antidepressants. The fourth issue (Vol.12, No.30, 2006) gave an overview of novel targets in the human brain for which radioligands had recently been developed: norepinephrine transporters, the enzyme cyclooxygenase-2, sigma-1, nicotinic and muscarinic receptors. The current issue is a continuation of issue 4. Several authors discuss the binding of radiopharmaceuticals to inflammatory cells. Such binding can be desirable (when infection imaging is the aim of patient scanning), but also be undesirable (when tumor detection is the primary aim). Dr. Doorduin and co-workers from the University of Groningen (The Netherlands) describe the efforts of several research groups to develop radioligands for peripheral benzodiazepine receptors (PBR) [1]. This target, which is currently called the mitochondrial 18 kD translocator protein (TSPO), is strongly overexpressed in activated microglia. PET imaging with specific PBR ligands can quantify neuroinflammation which plays a central role in the progression of neurodegenerative diseases. The PET technique can not only be employed to monitor disease progression, but also be an important tool in drug development, since therapy response and optimal drug doses can be non-invasively assessed. Dr. Chianelli and co-workers from the University of Rome Sapienza (Italy) and Radboud University, Nijmegen (The Netherlands) discuss the development of radioligands for SPECT imaging of infection [2]. Such ligands include peptides, human polyclonal antibodies, monoclonal antibodies, antibody fragments, antimicrobial agents, antimicrobial peptides and bacteriophages, labeled with ^99mTc, ¹²³I or ¹¹¹In. An important aim of this research is the development of a receptor-specific ligand that can be used for the imaging of infection and that allows a differential diagnosis between sterile and septic inflammatory processes. SPECT imaging with suitable radioligands can not only be used for diagnostic purposes but also in drug development. Drs. Van Waarde and Elsinga (Groningen, The Netherlands) give an overview of efforts to develop radiopharmaceuticals with greater tumor specificity than the currently used PET tracer, ¹⁸F-FDG [3]. Accumulation of FDG in inflammatory tissue can cause false classification as a nonresponder during anti-tumor therapy. Some proliferation markers (especially labeled nucleosides and amino acids) allow a better discrimination between tumor and inflammation, but for various reasons the specificity of such tracers will never reach 100%. Proliferation markers should therefore not be considered as replacements of FDG, but rather as useful additions to the imaging arsenal which can provide additional biochemical information for response monitoring and treatment planning. Dr. Van de Wiele and co-workers from the University Hospital Ghent (Belgium) and the Unversity Medical Center Groningen (The Netherlands) introduce the subject of tumor imaging using radioligands for growth factor or peptide receptors [4]. Such receptors are coupled to intracellular signaling pathways driving tumor cell proliferation and are therefore promising targets in anti-tumor therapy. Peptide and growth factor receptor imaging can be used in the drug discovery process, to assess whether drugs are reaching tumors in sufficient amounts and how rapid they are cleared from tumor tissue. In addition, noninvasive imaging techniques may allow the selection of patients that will benefit from receptor-targeting therapies and the measurement of treatment-induced receptor downregulation. Dr.Dijkers and co-workers from the University Medical Center Groningen (The Netherlands) review PET and SPECT imaging of the human epidermal growth factor receptor (HER2/neu), using monoclonal antibodies (mAbs) and various antibody fragments, labeled with positron emitters (⁶⁴Cu, ⁶⁸Ga, ⁸⁹Zr, ⁷⁶Br,¹²⁴I) or single-photon emitters (^99mTc,¹¹¹In,¹²³I, ¹³¹I) [5]. HER2/neu is a relevant target for therapy in breast cancer. The monoclonal antibody trastuzumab (Herceptin®) and the tyrosine kinase inhibitor lapatinib (Tykerb®) have been developed to target HER2/neu. Immunoscintigraphy of HER2/neu expression may play an important role in the improvement of diagnostic imaging, the guidance of monoclonal antibody-based therapy and the development of novel mAb-based drugs.