INVITEDPERSPECTIVE

The Importance of Kinetic Enhancement

Consider the importance of kinetic
enhancement of radiopharmaceuticals.
In the field of nuclear medicine,essentially everything relies on thedistribution or the regional kinetics ofan administered radiopharmaceutical.
In many cases, a picture of distribution
is enough to provide the needed clinicalor research information, or a quantitative measure of uptake into the tissue ofinterest may be needed to provide thedesired information. In the most complicated cases, the desired information
is obtained from analysis of the rates atwhich tracer accumulates or leaves one
or more organs, structures, or tissues.
See page 1378

Regardless of the particular method ofinterpretation, it is always desirable tohave a large amount of radiopharmaceutical located in the regions ofinterest and a small amount in thenontarget regions and especially theimmediate background regions. Various mechanisms, including diffusion,
lipid solubility, nontarget organ interactions, and metabolism, contribute to
the uptake kinetics and the observed
distribution of a radiopharmaceutical.
In addition, all radiopharmaceuticals
are susceptible to some degree ofassociation with the components ofthe blood. Most commonly, a loose
and rapidly exchanging lipophilic orhydrogen-bonding interaction takes
place with blood proteins or themembranes of blood cells. Serumalbumin and a1-acid glycoprotein in
Received Apr. 8, 2009; revision accepted
Apr. 14, 2009.
For correspondence or reprints contact: Marc
S. Berridge, 3D Imaging, LLC, and University of
Arkansas for Medical Sciences, P.O. Box 13267,Maumelle, AR 72113.
E-mail: mberridge@3dimagingllc.com
COPYRIGHT ª 2009 by the Society of Nuclear
Medicine, Inc.
DOI: 10.2967/jnumed.108.060905

particular provide loose associations
for many compounds. Some proteinsin the blood provide strong interactions for the transport of specific target
molecules. Radiopharmaceuticals canbe substrates for these as well. Wellknown examples include transferrin,
which binds cationic iron, providing
a mechanism for iron distribution, andalso has a strong affinity for thegallium used in radiopharmaceuticals.
Competition of transferrin for gallium
must be considered when designing
gallium-labeled radiopharmaceuticals(1–3). Similarly, the strong binding ofsex hormone–binding globulin to estrogen- and testosterone-based radiopharmaceuticals is a significant factor(4–6) in their biologic distribution andtherefore their usefulness as radiopharmaceuticals. Fortunately for thepractice of nuclear medicine, mostradiopharmaceuticals are susceptible
to only a weak or moderate affinity toalbumin and a1-acid glycoprotein,often in proportion to the lipophilicityof the radiopharmaceutical. The principle is well known anecdotally, although it has not been specificallyinvestigated in detail.
A weak affinity to blood components
has been assumed to have a smalleffect, if any, on ultimate radiopharmaceutical distribution. When equilibrium
is rapid between bound and free tracer
in the blood, most of the bound tracer
should be available to a tissue evenduring a single capillary pass, and all of
it would become available during thecourse of the uptake phase of a typicalradioimaging procedure. In most radiotracer kinetic modeling applications,moderate binding to serum proteinswould be expected to be manifested
only as a reduction of the rate constantof transport from the blood to thetissue. As the affinity of a tracer forblood components increases, the effecton the kinetics and distribution of thetracer would also be expected toincrease. There must therefore bea continuum of binding affinity ofradiopharmaceuticals to blood components, the effects of which on theultimate use of the tracer are not wellunderstood.
In this issue of The Journal of
Nuclear Medicine is a paper by Kuga
et al. titled ‘‘Competitive Displacement of Serum Protein Binding ofRadiopharmaceuticals with Amino AcidInfusion Investigated with N-Isopropylp-123I-Iodoamphetamine’’ (7). The paper represents a joint effort from 3
universities in Japan, the University ofMiyazaki, Kanazawa University, andIbaraki Prefectural University of Health
Sciences, and treats the effect ofradiopharmaceutical binding to serum
proteins on tracer kinetics and theresulting images. As an assessment ofradiopharmaceutical binding to proteins
and its manipulation, the work wasrigorously done. The association of theradiopharmaceutical with each of therelevant binding sites on serum proteins
was assessed individually. The effect ofintervention on the binding to eachbinding site was also measured. This
work is an example to those such as mewho have previously been reduced tohand waving with insufficient data whenserum protein binding has been a factor
in our radiopharmaceutical results. Thepaper focuses on serum protein bindingof the popular and successful cerebral
perfusion tracer, N-isopropyl-p-123Iiodoamphetamine (123I-IMP), but themethods these investigators have used
are generally applicable to the study of
any radiopharmaceutical. Their data
demonstrate that a large fraction of
123I-IMP is bound to serum proteins at
all times.
The study of the protein binding of
123I-IMP should be only a beginning.
Data are generally lacking on thebinding of radiopharmaceuticals toblood components. Kuga et al. havemade an interesting observation that inIMPORTANCE OF KINETIC ENHANCEMENT • Berridge1203

this case the binding of the radiopharmaceutical can be manipulated. In thiscase it is reduced by the administrationof amino acids, which compete withthe protein binding of 123I-IMP. Most
importantly, amino acids do this without competing with the target uptakeof the radiopharmaceutical. The result
is enhanced target uptake. A generaladvantage would exist to havingmethods that are acceptable for humanuse to reduce the nontarget uptake ofradiopharmaceuticals and to increase
uptake in target regions. Kuga et al.
point out that only a limited number of
discrete binding sites on serum proteins are responsible for much of theobserved binding of drugs to serum
proteins. The method of amino acidinfusion used in this work may
therefore be applicable to other radiopharmaceuticals that share this mechanism of protein binding. With thislogic, the work reported here can beviewed as the first steps into a generalarea of investigation. One might also
envision extension of the principle toradiopharmaceuticals that may bind inother ways. For the strategy to besuccessful, there must be an identifiable binding mechanism that interferes with distribution into the tissues.
There must then be a method capableof disrupting that binding and acceptable for human use. Finally, themethod of disruption of serum protein
binding must not also disrupt bindingof the radiopharmaceutical to its
target. Continuing work to understandthe dynamics of radiopharmaceuticalinteractions in serum and their effecton target uptake should be encouraged.
The paper opens new questions forinvestigation. An interplay seems to bepresent between tracer binding and thevarious binding sites in serum. The
binding percentage to individual serum components did not fit a simple
relationship to binding in whole serum. This finding may indicate a dy-1204

namic system and may be amenable tofurther analysis. However, the brain
uptake seems to indicate a system thatis more static. The relative increase inplasma free fraction of 123I-IMP wasnearly the same as the relative increasein brain uptake. This result would beexpected of a perfusion tracer whenuptake is driven only by the freeplasma concentration. If rapid equilibration existed between bound andfree 123I-IMP, effectively providing
access to the tissue for bound 123IIMP, one would expect a proportionately lesser effect on brain uptake
caused by a change in the plasma freefraction. Is equilibration simply slow
relative to capillary transit time?
Again, target organ uptake may beable to be modeled mathematicallyfrom the binding characteristics ofa tracer and of its inhibitors to carrier
proteins in the serum to allow a fuller
understanding and optimization of thisapproach. Binding of 123I-IMP toserum proteins was about 80% using
standard procedures. The normal free
fraction of 123I-IMP in plasma istherefore just over 20%. The reported
intervention with Proteamin 12X Injection (Tanabe Seiyaku Co., Ltd.)
succeeded in raising the available
fraction of tracer in plasma to nearly
30%, which still left fully 70% boundto serum proteins. Would it be possible
to increase the effectiveness of theintervention to tap this much larger
reservoir of radiopharmaceutical?
The improvement in 123I-IMP target uptake reported in this paper was
significant though moderate. It represents an interesting scientific observation and may lead to further workof increasing significance. In thisinstance, deposition in the brain due
to the intervention increased by about
30%, compared with standard procedures. Increases in liver and bladder
uptake were also observed. The enhanced uptake may allow for a concomitant reduction in the injected

dose or an improvement in image
quality for a clinical study. The
enhancement comes at the minor costof an added intervention in the formof administration of relatively large
doses of the amino acids that reduce
the serum binding of 123I-IMP. Similar interventions are commonplace;still, the clinician must make thedecision of whether the marginal
extra effort is worthwhile to obtainthe marginal improvement in image
quality or reduction in radiopharmaceutical dose. As this approach isrefined and expanded, we may hopefor substantial gains in the effectiveness of this and other radiopharmaceuticals, possibly allowing useful
results to be obtained from radiopharmaceuticals that might otherwise
be ineffective.
Marc S. Berridge
3D Imaging, LLC, and University of
Arkansas for Medical Sciences
Little Rock, Arkansas
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THE JOURNAL OF NUCLEAR MEDICINE • Vol. 50 • No. 8 • August 2009