Sharma Lab

Biomedical imaging plays a pivotal role in diagnosis and staging of diseases, drug discovery, characterization and validation of novel biomarkers, and guiding disease management (assessing drug efficacy, target specificity, improving prognosis, and stratification of patients). Our lab works at the interface of chemistry, medicinal chemistry, radiopharmaceutical science, biochemistry, and biology. Employing an interdisciplinary approach, we design and develop molecular imaging probes capable of interrogating important biochemical pathways across multiple disciplines. Although our research focus is not confined to any specific imaging modality, we frequently employ radiological molecular imaging, due to its high translational potential, for interrogating vital biochemical processes in cellulo and in vivo.

Chemical and Radiopharmaceutical Synthesis

Employing state-of-the-art rational drug design tools, we are interested in the synthesis of small organic molecules, peptide conjugates, and metalloprobes to interrogate important biological pathways and identify new biomarkers. Other areas of near term interests are to extend the repertoire of our reporter probes into various biological applications via development of novel heterocyclic compounds for imaging reporter gene expression and cancer biology, chemiluminescent substrates for imaging inflammation, and near infrared optical probes for understanding critical disease-specific biochemical mechanism(s).

Multidrug Resistance and Blood-Brain Barrier Imaging

P-glycoprotein (Pgp), the product of the human multidrug resistance gene (MDR1), remains a well-characterized biomarker of chemotherapeutic resistance, oral-bioavailability of drugs, and is a critical target for biomedical imaging. It is a 170 kDa plasma membrane protein, a member of the ABC (ATP-binding cassette) family of transporters, and postulated to decrease intracellular accumulation of moderately hydrophobic and cationic species. Pgp is naturally expressed in several human tissues responsible for protective and excretory functions. Importantly, emerging biochemical models of β-amyloid (Aβ) efflux pathways at the blood-brain barrier, implicate a critical role for Pgp in progression of Alzheimer's disease and other neurodegenerative disorders. Finally, overexpression of MDR1 Pgp contributes to resistance of a broad spectrum of structurally diverse cytotoxic drugs. For interrogation of therapeutic agents likely to benefit patients undergoing chemotherapy, a noninvasive method to evaluate the functional status of P-glycoprotein activity in vivo would be desired.

Towards this goal, our lab has identified a lead agent capable of single photon emission computed tomography (SPECT)/positron emission tomography (PET) imaging for assessingMDR1 Pgp functional transport activity in vivo.

Alzheimer’s Disease Imaging

Among various neurodegenerative diseases, 4.5 million Americans are believed to have Alzheimer's disease (AD) and by 2050, the number could increase to 13 million. It appears that life expectancy and the incidence of AD seem to be moving hand-in-hand. The present annual cost of $100 billion is expected to reach $400 billion by 2025, thereby exerting a considerable burden on the national healthcare infrastructure. Several pharmaceutical companies are working on design and development of therapeutics for treatment of patients suffering from AD. While a wonderful therapeutic drug continues to be a distant dream, several biomarkers have been identified as possible targets. For assisting drug discovery, diagnostic imaging could have wide applications in premortem diagnosis and monitoring of new disease-modifying therapeutics.

Our group actively seeks positron emission tomography (PET) and single photon emission computed tomography (SPECT) diagnostic agents that are capable of evaluating noninvasively the presence of β-amyloid (Aβ) aggregates and other proteins in vivo. Our objective is to identify PET/SPECT agents capable of identifying AD at earlier stages, prior to its full clinical expression. We are specifically interested in design and development of highly sensitive and specific imaging probes wherein PET imaging data on disease staging is in accord with globally accepted criteria of clinical dementia ratings (CDR).

Myocardial Perfusion Imaging

Myocardial perfusion imaging (MPI), a versatile tool for clinical diagnosis, plays an important role in the noninvasive measurement of coronary artery disease (CAD). Currently, common single-photon emission computed tomography (SPECT) MPI agents for determining myocardial blood flow (MBF) in patients comprise 201Tl or 99mTc-complexes, such as99mTc sestamibi and 99mTc-tetrofosmin. However, SPECT imaging agents have inherent limitations, including the continuing threat of serious shortages of 99mMo/99mTc-generators. Additionally, current SPECT tracers also suffer from shortcomings in pharmacokinetics, low myocardial first-pass extraction, redistribution of the radiotracer to non-targeted tissues over time, and non-linearity of radiotracer uptake at elevated blood flow (the "roll-off" phenomenon). By comparison, positron emission tomography (PET) provides technical advantages, including higher spatial resolution, improved attenuation correction, and the capability to perform quantitative measurements at the peak of stress. Commonly employed PET MPI tracers are: 82RbCl, 13NH3, and H215O. However, the utility of these agents is limited due to their short physical half-life (less than 10 minutes), which pose difficulties for easy access to these agents. Additionally, a few promising 18F-labeled agents, such as mitochondrial membrane potential probe 18F-BnTP and mitochondrial complex I inhibitors18F BMS-747158, 18F-10, 18F-RP1004, and 18F-MCI27, have also emerged as promising leads. However, aside from biochemical properties of various strengths and weaknesses, these agents also depend on an 18F-based radiopharmaceutical distribution model, which may not readily apply to all sites within the U.S. or other countries in the world. Thus, PET tracers demonstrating high myocardial first pass extraction, and rapid excretion from adjoining organs, while incorporating generator-produced, rather than cyclotron-produced, isotopes could potentially enable portable technologies, facilitating wide access to PET MPI agents.

Through structure-activity relationships (SAR), we have identified a lead PET agent that penetrates myocardium cells, localizes into mitochondria, and displays promising characteristics as a noninvasive MPI probe in vivo. Further validations and characterization in nonhuman primates are in progress.