Current Medicinal Chemistry - Volume 21, Issue 1, 2014

The number of Asialoglycoprotein (ASGP) receptors on the hepatocytes of patients with liver disease is reduced and is thus considered a good indicator for the evaluation of liver function. ASGP receptor-targeted radiopharmaceuticals permit a non-invasive way to evaluate total and regional hepatic function and hepatic functional reserve visually and quantitatively. Over the past three decades, a variety of ASGP receptor-targeted probes have been developed with different molecular backbones (albumin, polymer, small-molecular-weight ligand), different glycol-residues (galactose, lactose, N-acetyl-galactosamine) and different chelating systems suitable for radiolabeling with SPECT isotopes (99mTc, 111In, 67Ga, 131/125I, 153Sm) and PET isotopes (68Ga, 18F). In this review, we present an overview of ASGP receptor-targeted radiopharmaceuticals, discuss their chemistry, biodistribution, catabolism and challenge as well as application for measurement of liver function.

Glucose is an important molecule for metabolism. It is more actively taken up in tumor cells than in normal cells, thus making it possible to detect the tumor. Radiolabeled glucose derivates have been successfully employed for tumor imaging for several decades. This review focuses on the development of various radiolabeled glucose derivatives as tumor imaging probes with single photon emission computed tomography (SPECT) and positron emission tomography (PET) and discusses basic research data, current status and future prospects of this class of imaging agents.

It is widely accepted that sigma ( σ) receptors represent a new and different avenue in the possible pharmacological treatment of cancer and several brain-related disorders. Of the two different σ receptor types the σ1 receptors are assumed to be of major impact for brain diseases. Molecular imaging of brain σ1 receptors with positron emission tomography (PET) or single photon emission computed tomography (SPECT) may provide a significant contribution to the understanding of the cross-talk between σ1 receptors and inter- and intracellular signalling systems. New insights into these functional interrelationships will allow a better diagnosis of brain and cancerous diseases and direct a rational development of new therapeutic concepts.

Serotonin and its various receptors are involved in numerous brain functions and neuropsychiatric disorders. The 5-HT1A family is the best characterized subtype of the fourteen currently known 5-HT receptors. The 5-HT1A receptor is closely involved in the pathogenesis of anxiety, depression, epilepsy and eating disorders and therefore is an important target for drug therapy. The development in the 1980s of molecules specifically targeting this receptor was followed by the rapid development of corresponding PET neuroimaging. Because this receptor represents a crucial target in neuroscience, a large number of radioligands have been developed by academic and industry centers for visualization and quantification, first in living animals and ultimately in humans. After a brief account of some of the structural and functional characteristics of brain 5-HT1A receptors, this review focuses on the main lines of evolution opened up by preclinical and clinical 5-HT1A PET radiopharmaceuticals, illustrating the potential value of PET for clinical research and drug development.

The deposition of β-amyloid (Aβ) plaques in the parenchymal and cortical brain is accepted as the main pathological hallmark of Alzheimer’s disease (AD). According to the amyloid cascade hypothesis, the Aβ deposition in the brain appears to be a good diagnostic biomarker for AD and may also be a good predictive biomarker of this disease. Molecular imaging of Aβ plaques in the brain with positron emission tomography (PET), single photon emission computed tomography (SPECT) or molecular optical imaging represents a promising approach to the early diagnosis of AD and monitoring the effectiveness of novel therapies for this devastating disease. Our review focuses on the past and recent knowledge in this field with respect to small organic molecules that have been utilized for the development of Aβ imaging probes.

The metabotropic glutamate 1 receptors (mGluR1) have been shown to play a role in neuropathic pain and neurological and psychiatric disorders such as ischemia, epilepsy, anxiety, as well as schizophrenia and other cognitionrelated disorders. As a result, mGluR1 has been an important target for drug development. As a radiotracer-based in vivo imaging technique Positron Emission Tomography (PET) is an important tool in the investigation of receptor function in the living brain under normal conditions and its dysfunction in diseases, as well as in the study of receptor occupancy by experimental therapeutic agents. In this report we review the development and evaluation of PET radiotracers for mGluR1 and provide an assessment of the tracers that are likely to succeed in the imaging and quantification of mGluR1 in humans.

Nanoparticles can be near infrared (NIR)-fluorescent (e.g., gold nanoparticles, quantum dots or carbon nanotubes) or can have magnetic properties (e.g., iron oxide nanoparticles). These optical or magnetic properties can be exploited for use in thermal therapy and molecular imaging. Radiolabeled nanoparticles have proven to be promising tools in the diagnosis and therapy of malignant processes due to their multivalency and as multi-modal imaging agents. Furthermore, these radiopharmaceuticals may function simultaneously as both radiotherapy systems and thermal-ablation systems. This review examines the application of radiolabeled nanoparticles in the development of multifunctional nanosystems for targeted therapy.

A series of radiolabeled peptides have been designed and optimized for tumor-targeted peptide receptor radionuclide therapy (PRRT). Pre-clinical and clinical applications of PRRT have shown promising results on tumor response, overall survival, and quality of life in patients with several kinds of tumors. 90Y-DOTA-TOC and 177Lu-DOTA-TATE are two of the most common radiopharmaceuticals with symptomatic improvements and complete clinical data. In addition to somatostatin analogs, radiolabeled peptides have been developed to target the relative receptors overexpressed in the tumors, such as integrin αvβ3, gastrin-releasing peptide receptor (GRPR), melanocortin-1 receptor (MC1-R), cholecystokinin (CCK) receptor, and glucagon-like peptide-1 receptor (GLP-1R). Several strategies have been designed to improve the therapeutic efficacy of PRRT. For instance, radiolabeled peptides could be optimized by the amino acid modification and radionuclide selection. Healthy tissue protective agents and multi-cycle procedures could effectively decrease the side effects of PRRT. Furthermore, combination treatments, including PRRT combined with surgery, chemotherapeutic agents, or radiosensitizing agents could be applied to increase the effectiveness of PRRT. In this review, the current progress of peptide-based radiopharmaceuticals for tumor-targeted PRRT was summarized. Radiopharmaceuticals currently under clinical investigation were also described.