Barbara E. Francis

Non-invasive radiotracer imaging as a tool for drug development.

Non-Invasive Radiotracer Imaging (NIRI) uses either short-lived positron-emitting isotopes, such as 11C and 18F, for Positron Emis ion Tomography (PET) or single photon emitting nuclides, e.g., 123I, which provide images using planar imaging or Single-Photon Emission Computed Tomography (SPECT). These high-resolution imaging modalities provide anatomical distribution and localization of radiolabeled drugs, which can be used to generate real time receptor occupancy and off-rate studies in humans. This can be accomplished by either isotopically labeling a potential new drug (usually with 11C), or indirectly by studying how the unlabelled drug inhibits specific radioligand binding in vivo. Competitive blockade studies can be accomplished using a radiolabeled analogue which binds to the site of interest, rather than a radiolabeled version of the potential drug. Imaging, particularly PET imaging, can be used to demonstrate the effect of a drug through a biochemical marker of processes such as glucose metabolism or blood flow. NIRI as a development tool in the pharmaceutical industry is gaining increased acceptance as its unique ability to provide such critical information in human subjects is recognized. This section will review recent examples that illustrate the utility of NIRI, principally PET, in drug development, and the potential of imaging advances in the development of cancer drugs and gene therapy. Finally, we provide a brief overview of the design of new radiotracers for novel targets.

[125I] 3-quinuclidinyl 4-iodobenzilate: A high affinity, high specific activity radioligand for the M1 and M2-acetylcholine receptors

We have prepared a radioiodinated ligand which binds with high affinity to the muscarinic acetylcholine receptor (m-AChR). A derivative of 3-quinuclidinyl benzilate, [125I] labeled (R) 1-aza-bicyclo(2.2.2)oct-3-yl (R,S)-alpha-hydroxy-alpha-(4-[125I]iodophenyl)phenyl acetate (4- IQNB ) exhibits an affinity for the m-AChR from corpus striatum higher than that of (R) [3H] QNB. Additionally, [125I] 4- IQNB exhibits receptor selectivity for the M1 receptor since the affinity for the receptor from dog and rat heart is lower than that using dog or rat corpus striatum.

[77Br]-17-α-Bromoethynylestradiol: In vivo and In vitro characterization of an estrogen receptor radiotracer

Abstract [ 77 Br]17-α-Bromoethynylestradiol has been prepared by direct, no-carrier-added bromination of 17-α-iodoethynylestradiol. The product thus obtained has an effective specific activity up to 185 Ci/mmol and an association constant( K A ) of 7.1 × 10 9 M −1 . In vivo distribution studies indicate accumulation in rat uterus to the same levels as [ 3 H]E 2 (10% dose/g wet weight) and a target to blood ratio of 5–6.

The use of tritium labeled compounds to develop gamma-emitting receptor-binding radiotracers.

In an effort to evaluate receptor binding drugs for their potential as gamma labeled radiopharmaceuticals suitable for clinical heart scanning, in vivo data were compared with the results obtained from a theoretical model. The distribution of selected tritium-labeled, receptor-binding radiotracers was studied in animals to determine if the heart to blood ratios agree with those obtained using a theoretical model of receptor binding. In general, the in vivo studies agree with the theoretical model when the concentration of the radiotracer in the heart is due to specific receptor binding. The use of the theoretical model for a first approximation followed by in vivo biodistribution studies is an efficient strategy to select those few from among the large number of receptor binding compounds that will ultimately yield an efficacious radiopharmaceutical to study receptor changes in the intact human heart.