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Imaging Q&A

  •   Have tangible strides been made in using PET scanning to study brain receptor occupancy? Has the tool helped make dosage decisions easier in trials for Alzheimer’s and other CNS drugs?

    Yes, tangible strides have been made for both Alzheimer’s disease and other CNS Drugs. Two examples follow:

    1) For Alzheimer’s disease, tangible strides were made as early as the year 2000. Cerebral histamine H1 receptor binding was measured in vivo in 11 normal subjects (six young and five old) and 10 patients by positron emission tomography (PET) and [11C]doxepin, a radioligand for H1 receptors (Higuchi et al., 2000, Ref. 1). The parametric images describing the tracer kinetics were generated by either compartmental or graphical analysis. Images were examined statistically on region-of-interest and voxel-by-voxel bases. The binding potential of H1 receptors showed a significant decrease particularly in the frontal and temporal areas of the Alzheimer’s disease brain compared to the old, normal subjects. In addition, the receptor binding correlated closely to the severity of Alzheimer’s disease assessed by the Mini-Mental State Examination score within several brain areas. The ratio of K1 values between the brain areas and the cerebellum was used as a relative measure of regional cerebral blood flow which decreased in the frontal and temporal areas of the Alzheimer’s disease brain. However, the difference in the binding potential (i.e., the total concentration of receptor/equilibrium dissociation constant) between the Alzheimer’s disease patients and the old, normal subjects was greater than that in the cerebral blood flow, and the rate of decrease in the binding potential with the progression of Alzheimer’s disease was greater than the rate of decrease in the cerebral blood flow.

    This study demonstrated a predominant disruption of the histaminergic neurotransmission in the neurodegenerative processes of Alzheimer’s disease. This study suggested that the decline of the histamine receptor binding might play a substantial role in the cognitive deficits
    of Alzheimer’s disease patients

    2) For CNS drugs, tangible strides were made as early as 2001 (Tagawa et al., 2001, Ref. 2). Sedative characteristics are well-known in clinical and over-the-counter (OTC) medications. Sedation is caused by their penetration into CNS through the blood-brain barrier and the consequent occupation of histamine H1-receptors. The binding potential of doxepin (BP=Bmax/Kd) for available brain H1-receptors was imaged on a voxel-by-voxel basis through graphical analysis. By setting regions of interest, the H1-receptor occupancy of drugs was calculated in several H1-receptor rich regions.

    This study demonstrated the possibility of predicting H1-receptor occupancy by (+)-chlorpheniramine from its plasma concentration.

    References:
    1) M. Higuchi, K. Yanai, N. Okamura, K. Meguro, H. Arai, M. Itoh, R. Iwata, T. Ido, T. Watanabe and H. Sasaki. Histamine H1 receptors in patients with Alzheimer’s disease assessed by positron emission tomography. Neuroscience Volume 99, Issue 4

    2) M.Tagawa, M. Kano, N. Okamura, M. Higuchi, M. Matsuda, Y. Mizuki, H. Arai, R. Iwata, T. Fujii, S. Komemushi, T. Ido, M.i Itoh, H. Sasaki, T. Watanabe, and K. Yanai. Neuroimaging of histamine H1-receptor occupancy in human brain by positron emission tomography (PET): A comparative study of ebastine, a second-generation antihistamine, and (+)-chlorpheniramine, a classical antihistamine. Br J Clin Pharmacol, 52, 2001, pp. 501-509.

  •   With so many disciplines involved, what unique training and background should be required for clinical molecular imagers?

    The curriculum in clinical molecular imaging usually emphasizes these major components:

    1) PET

    2) Radioimmunotherapy and

    3) Structural imaging

    When working with these state-of-the-art techniques, it is important to evaluate the application of imaging in the management of multiple disease states. Here at WorldCare Clinical, our clinical trials encompass a wide diversity of radiopharmaceuticals in pursuing therapeutics for diseases where there are none.

  •   What are the one or two, in your opinion, most promising novel imaging techniques emerging in Phase I and II studies, and which therapeutic areas do they have the greatest potential?

    In Phase I and Phase II studies, dynamic-contrast enhanced magnetic resonance imaging (DCE-MRI) has shown promise in studying the pathophysiology of tumors. We currently measure tumor mass shrinkage to help determine potential efficacy, but DCE-MRI actually allows us to see changes in tumor vascularity by helping to measure blood flow in tissues and provide insight into vascular morphology. And because vascularity occurs at an earlier stage in tumor treatment than does shrinkage, DCE-MRI has the potential to enable earlier assessment of the response or failure of a particular drug. The possibilities here are extremely promising so far.

  •   What are the chief concerns regulators have regarding the use of data from independent imaging assessment committees in helping make endpoint decisions in oncology trials?

    Regulators are primarily concerned with ensuring that all data is obtained independent from sponsor or imaging CRO bias and with minimal variability. Particularly important is the complete blinding of all clinical data provided to the endpoint assessment committee (EAC). The sponsor must be able to prove that all procedures adhere to pre-defined, study-specific guidelines that address the roles of all participating players (i.e. blinded primary and secondary readers, adjudicators, etc.) and document how exactly the EAC determined and adjudicated the outcome. Clear and explicit procedural directives are crucial. And just as in any other trial, they demand data accrued in compliance with good clinical practices, which means electronic back-up, minimal deviation from instructions, and a transparent audit trail for the entire process.