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Dear Colleagues:
I am moderating (along with Brian Moyer) a round table discussion on "Matching Imaging System(S) to Your Biologic -How to Pick the Right Tools" this session will be held on Wednesday May 19, 2010 between 10.30-12.00 pm details can be found at http://staging.nxtbook.com/nxtbooks/aaps/nbc2010_preprogram/stage.php#/14
Imaging platforms are becoming a major tool in the elucidation of mechanisms of action, biodistributions of drugs and biologics, and one of the major advantages is many of the techniques afford a non-invasive mechanism to explore the ongoing biology in the same subject. Observing the biodistribution of a biologic or drug over time and providing coincident-in-time metabolic or pharmacodynamic information in the same subject is the goal. The regulatory agencies are supportive of these processes and tools and with proper validation can provide essential non-clinical and clinical pharmacokinetic and pharmacodynamic information. The goal of this session is to explore specific tools such as GFP, Quantum dots, NIR dye conjugates, MRI and fMR functional neuroimaging, PET and SPECT radiotracer imaging, and CT anatomical imaging as overlay informational imaging for more rapid analysis and understanding of toxicological effects and early detection of efficacy such as tumor metabolic or chemical change prior to changes i
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The following message was posted to: PharmPK
Re: Round table discussion on "Matching Imaging System(S) to Your
Biologic -How to Pick the Right Tools"
Dear Dr. Cheruvu
Following your request. Here are points for consideration and discussion:
1) Tools - Many of the methods in current use are inadequate for target
recognition. Identification of specific sites (TARGETs, SITES of
ACTION) - frequently such high-specificity sites are low-capacity
receptor sites. 2) Dose - if a high dose is given, mainly unspecific
high capacity sites may be recorded and specific sites missed,
overshadowed, obscured by nonspecific depositions.
3) Sensitivity - common in vivo procedures have low sensitivity and low
resolution (similar radio-assays and whole body autoradiography )
4) Resolution - For full information on organ and tissue distribution,
cellular resolution with specific tissue relationships is required.
Common low resolution imaging procedures may provide false negatives.
COMPARATIVE STUDIES have been revealing. 5) Microdosing - Current ADME
procedures are inadequate because of low sensitivity and low
resolution. 6) Validation of method - BEFORE (!!) introducing an
imaging method, validation with two compounds known localized should
be done (for instance with estradiol or vitamin D; both compounds are
now known to have target tissues in brain, spinal cord, heart, skin ,
etc) to provide evidence for the degree and kind of information
possible.
7) The picture is the evidence.
8) The label of a compound must not change its binding properties
(changes are possible with large atoms (Fluor, Iodine, or fluorescing
conjugates). This requires adequate controls as well.
Each point mentioned would require elaboration. Related references
below with discussions of above mentioned problems:
Stumpf WE. Memo to the FDA and ICH: appeal for in vivo drug target
identification and target pharmacokinetics. Recommendations for
improved procedures and requirements. Drug Discov Today. 2007
Aug;12(15-16):594-8.
Stumpf WE.The main role of vitamin D: seasonal regulation of vital
functions. High-resolution target recognition leads to a new paradigm
and advanced drug development. Eur J Drug Metab Pharmacokinet. 2007
Jan-Mar;32(1):1-6.
Stumpf WE.The dose makes the medicine.Drug Discov Today. 2006
Jun;11(11-12):550-5.
Walter E Stumpf: Drug Localization in Tissues and Cells. Receptor
Microscopic Autoradiography.ISBN 0-9740515-0-0. IDDC-Press, Chapel
Hill, NC. 2003. UNC Student Stores (eisdorfer.-a-.unc.edu).
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The following message was posted to: PharmPK
Walter:
There is at least one significant error in your response to Narayan Cheruvu that needs correction:
You say in #8: The label of a compound must not change its binding properties
(changes are possible with large atoms (Fluor, Iodine, or fluorescing conjugates).
Fluorine is NOT a large atom. Indeed, the van der Waals radius of 19F is only slightly larger than that of 1H (1.35 vs 1.2) and that is perhaps one of the reasons why fluorine is such a good pharmacophore. And as far as the specific use of fluorine for the noninvasive measurement of drugs, it has the unique 18F/19F pair, allowing fluorinated agents to be measured very effectively using either positron emission tomography (PET) or NMR spectroscopy.
-- Professor Walter Wolf, Ph.D.
Distinguished Professor of Pharmaceutical Sciences
Director, Pharmacokinetic Imaging Program
Department of Pharmaceutical Sciences, School of Pharmacy
Chair, Biomedical Imaging Science Initiative
University of Southern California
1985 Zonal Ave., Los Angeles, CA 90089-9121
E-Mail: wwolfw.-a-.usc.edu
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It is an (old) trick that medicinal chemists use to block metabolism on a particular (aromatic) carbon atom to replace H by F. This is often well-tolerated because of the small steric effect of fluorine (i.e. it is small).
Frederik
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Dear Frederik and Walter,
Replacing an H for a F on a ligand molecule does not always keep the biological activity of a molecule. Sometimes it does, sometimes it does not. You cannot assume either way unless you demonstrate it by making and testing the cold compound.
Biological activity depends on much more than just two atoms having similar "sizes".
Dario
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Dario:
I agree. But the discussion in this thread is not focused primarily on biological activity, but on imaging. The point I had questioned in Walter Stumpf's message of 4/23 was lumping fluorine (a small atom, close to 1H) with iodine (a much larger molecule), or even larger substituents (fluorescing conjugates).
Inasmuch as the biological activity of a molecular species is the result of a number of determinants - transport, uptake, metabolism - structural features that enhance any of these processes will help, and any structural features that will hinder will affect biological activity in a negative manner. It is important to consider the total system, and not assume that any one feature provides ALL the information. That is why imaging is such an important tool: it allows us to MEASURE what is happening in the living system, not just ass-u-me.
-- Professor Walter Wolf, Ph.D.
Distinguished Professor of Pharmaceutical Sciences
Director, Pharmacokinetic Imaging Program
Department of Pharmaceutical Sciences, School of Pharmacy
Chair, Biomedical Imaging Science Initiative
University of Southern California
1985 Zonal Ave., Los Angeles, CA 90089-9121
E-Mail: wwolfw.-a-.usc.edu
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The following message was posted to: PharmPK
Response to Walter Wolf:
A 'significant error'? - as commented by Walter Wolf. But where is the
error, - who is in error? Dr. Doller's comment supports the cautionary
remark that I made (in number 8 of problems to be considered in
imaging) referring to possible changes of biological activity of a
tagged molecule, the need for validation and high- resolution
complementation of current procedures. As stated by Dario Doller:
'Sometimes it does, sometimes it does not'. Yes, ' you cannot assume
either way, unless you demonstrate it by making and testing the cold
compound.' There is published evidence of such changes of binding
affinities for radio-iodine as well as for fluorescing conjugates.
As regards specifically F-18, R.Hochberg writes (pers. comm.): ' - it
sometimes increases binding affinity and is a very stable label -
nevertheless you cannot predict the effect of binding, and receptor
affinity studies must be done with non-radioactive ligand.- we have
some publications on this with glucocorticoids -.'
About two years ago I challenged Walter Wolf about controls with a
compound known localized, eg., estradiol. Walter Wolf referred to
whole body autoradiographic (albeit deficient because of low
resolution) supposedly done by Dr. Katzenellenbogen and separately by
Dr. Whitby. No evidence has been provided yet, however.
Again, in vivo imaging is very important. But the data should be
validated and in some cases complemented and correlated with results
from high cellular and tissue resolution approaches to avoid mis- and
over-interpretation.
Walter E Stumpf
www.walterstumpf.com
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The following message was posted to: PharmPK
One would expect drug properties (i.e. binding affinities, metabolism,
both qualitative and quantitative) to change with larger labels such as
"radio-iodine" and "fluorescing conjugates". Smaller atoms (e.g.
fluorine) may cause smaller changes or no change at all. Obviously, one
needs to validate any changes made to a drug for the purpose of imaging
or otherwise. It is noteworthy that even changing hydrogen to deuterium
one can introduce significant changes in drug properties. For example,
see check out these links in Nature:
http://www.nature.com/news/2009/090415/full/458817a.html
http://www.nature.com/uidfinder/10.1038/458269a
Best regards,
Frederik Pruijn
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The following message was posted to: PharmPK
The comments by Frederik B. Prujin are relevant, and they highlight the need to distinguish between imaging methods that capture drug pharmacokinetics and those that capture drug pharmacodynamics.
Let me reinforce one point: when we want to measure the pharmacokinetics of drugs at their target or toxicity sites, using noninvasive imaging, ANY chemical change of that drug will not really study that drug, but an analog. Thus, the radiolabeling that should be considered is intrinsic - using a radioisotope of an element already present in that molecule. This, radiolabeling a fluorinated drug with 18F does NOT change the chemical nature of the drug. For most drugs, 11C (replacing one or more of the existing 12C atoms) will be the tool of choice for imaging, and 14C for destructive laboratory measurements. Special cases, such as the platinated drugs, can be intrinsically radiolabeled with 195mPt.
Like in any study, the key is to determine what is the question we are trying to answer, and does the method we are proposing to use effectively and appropriately answer that question.
-- Professor Walter Wolf, Ph.D.
Distinguished Professor of Pharmaceutical Sciences
Director, Pharmacokinetic Imaging Program
Department of Pharmaceutical Sciences, School of Pharmacy
Chair, Biomedical Imaging Science Initiative
University of Southern California
1985 Zonal Ave., Los Angeles, CA 90089-9121
E-Mail: wwolfw.-a-.usc.edu
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