SCIENCE ISSUES: What are the characteristics of a good PET imaging probe? How can we facilitate probe development?

5/20/02


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SCIENCE ISSUES: What are the characteristics of a good PET imaging probe? How can we facilitate probe development?

Noninvasive Functional Imaging drug delivery to target (kinetics, PK) assess modulators of delivery (transport) drug impact on target (dynamics, PD) inhibit enzyme, process, receptor angiogenesis, blood flow, energetics

Why Do We Want to Image Proliferation/DNA Synthesis? ? general tissue response to injury ? for tumors, an index of turnover

Imaging Proliferation (DNA Synthesis) Thymidine or Analogs dTMP ? ? DNA (TK) ? dThd 1. Direct use of circulating dThd for DNA synthesis provides a potential probe. 2. In the lab, when 3H-dThd added, it’s interpreted as “labeling-index” or “proliferation marker.” 3. Can also use BUDR, IUDR, FIAU, FMAU.

Clinical Interest in 11C-dThd for Imaging 1972 Christman Initial Proposal 1988 Martiat Tested in NHL 1992 van Eijkeren Head & Neck 1994 Vander Borgt Brain Tumors 1998 Shields Lung Tumor

Thymidine as a Proliferation Marker Drawback: dThd ?Thy ? ? bicarbonate; CO2 Rapidly & extensively catabolized (radiolabeled products circulating as “background noise”) Practical Alternatives to dThd: -- Must Block Catabolism -- While Retaining Anabolism

PET Imaging: Proliferation Markers

CELL CULTURE DATA SHOWS: dTMP ? ? DNA (TK) ? dThd FMAUMP ? ? DNA (TK)? FMAU FMAU readily enters cells FMAU phosphorylated by TK to FMAUMP FMAUMP incorporated into DNA Extract DNA,digest,measure FMAU by HPLC

Shields J.Nucl.Med (1998) 11C-thymidine {TdR or dThd} Patient with lung tumor (upper arrow) Vertebral marrow (lower arrow)

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How Can a Consortium of Academia/Industry/Government Facilitate Nonclinical Aspects of PET Imaging Probe Development?

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Author: CDER User