Letters
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 6 1089
References
Aâ40-fibrils, as well as its impact on the in vivo pharmacoki-
netics. We found that introduction of fluorine in the 5-position
as well a formal substitution of 3′-H for F, Cl, Br, and CH3 is
compatible with pertaining a relevant affinity for Aâ. It was
seen that 3′-Cl and -Br provided increased affinity relative to
the H-analogues. An increased Aâ40 affinity of BTAs as a result
of 3′-I substitution has been observed by other investigators.14
Further, a fluorine substituent in the 5-position on the ben-
zothiazole ring in combination with 3′-CH3 or 3′-Cl significantly
increased the metabolic stability relative to the reference [11C]-
PIB. Judged from the in vivo data obtained with the two leads,
[11C]25 and [11C]26, we demonstrated that the brain uptake
kinetics of N4′-11C-methylated BTAs are controlled also by the
metabolic stability of the compound.
We assessed brain uptake of the radiolabeled derivatives in
wild type Balb-C mice without brain amyloid deposits. Thus,
this study reflects brain entry and clearance from normal brain
tissue. For imaging of Aâ in vivo, a high binding affinity, high
brain entry, and low nonspecific binding in the brain will
generally improve the information extracted from imaging
protocols by increasing the signal-to-noise ratio. The requirement
of rapid clearance from normal brain tissue is particularly
important for PET ligands labeled with the short-lived 11C (t1/2
) 20.3 min). Previous studies5,14 have emphasized the impor-
tance of providing a 11C-labeled tracer of relatively low
lipophilicity. Based on the 2 min/30 min uptake ratios found in
this work (Table 1), it is indicated that a high lipophilicity (Log
Poct/PBS ∼ 3) is not necessarily limiting. However, the optimum
metabolic stability and overall brain uptake kinetics for BTA-
based Aâ-imaging agents is yet to be established.
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In summary, six novel N-11C-labeled BTAs have been
synthesized and screened for brain uptake and metabolic
stability. It was found that the substitution pattern of the phenyl
ring and the benzothiazole moiety has influence on the metabolic
stability. The metabolic stability of the compounds in turn has
an effect on the uptake of radioactivity in brain tissue. Two
leads have been identified for which the increased metabolic
stability has been found to lead to improved brain uptake
kinetics. Work in transgenic animal models is in progress to
further investigate whether the metabolically stabilized 5-,3′-
substituted BTAs can provide improved specificity of the signal
and facilitate a more precise quantification of the tracer kinetics.
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Acknowledgment. Financial support was received from the
German Research Council HE4560/1-2.
Supporting Information Available: General methods, experi-
mental procedures, 13C NMR shift values for reference compounds,
determination of purity of test compounds, determination of Ki
values, biodistribution in mice, and metabolite analysis. This
material is available free of charge via the Internet at http://
pubs.acs.org.
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