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Review
, 63 (7), 539-46

Approaches Using Molecular Imaging Technology -- Use of PET in Clinical Microdose Studies

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Review

Approaches Using Molecular Imaging Technology -- Use of PET in Clinical Microdose Studies

Claudia C Wagner et al. Adv Drug Deliv Rev.

Abstract

Positron emission tomography (PET) imaging uses minute amounts of radiolabeled drug tracers and thereby meets the criteria for clinical microdose studies. The advantage of PET, when compared to other analytical methods used in microdose studies, is that the pharmacokinetics (PK) of a drug can be determined in the tissue targeted for drug treatment. PET microdosing already offers interesting applications in clinical oncology and in the development of central nervous system pharmaceuticals and is extending its range of application to many other fields of pharmaceutical medicine. Although requirements for preclinical safety testing for microdose studies have been cut down by regulatory authorities, radiopharmaceuticals increasingly need to be produced under good manufacturing practice (GMP) conditions, which increases the costs of PET microdosing studies. Further challenges in PET microdosing include combining PET with other ultrasensitive analytical methods, such as accelerator mass spectrometry (AMS), to gain plasma PK data of drugs, beyond the short PET examination periods. Finally, conducting clinical PET studies with radiolabeled drugs both at micro- and therapeutic doses is encouraged to answer the question of dose linearity in clinical microdosing.

Figures

Figure 1
Figure 1
Different degree of blood-brain barrier penetration of three different radiolabeled drugs revealed by PET measurements in humans (A: [18F]ciprofloxacin; B: racemic [11C]verapamil; C: [11C]ST1859). Shown are transaxial PET summation images depicting radioactivity distribution in brain for the duration of the PET scan after iv administration of the radiolabeled drug. The radiation scale is set from 0 to 0.5 (A) and 0 to 2.0 (B, C) standardized uptake value (SUV). PET images were recorded on an Advance PET scanner (General Electrics Medical Systems). The chemical structures of each drug are shown above the PET images.
Figure 2
Figure 2
(A) Coronal and horizontal PET summation images depicting the distribution of the radiolabeled dual P-gp/BCRP inhibitor [11C]tariquidar in rat brain after administration of a microdose (0.002 mg/kg, upper panel) and after administration of a microdose preceded by an iv therapeutic dose (15 mg/kg, given 2 h before radiotracer injection) (lower panel). The radiation scale is set from 0.05 to 2.0 standardized uptake value (SUV). PET images were recorded on a microPET Focus220 scanner (Siemens, Medical Solutions). (B) Time-activity curves (mean SUV±SD) of [11C]tariquidar in whole brain after administration of an iv microdose (open squares) and an iv microdose preceded by an iv therapeutic dose (15 mg/kg) (filled diamonds) in 3 naïve rats. The chemical structure of [11C]tariquidar is shown on top of the graph.
Figure 3
Figure 3
(A) Transaxial PET summation images depicting radioactivity distribution in brain in one subject after administration of an iv microdose of (R)-[11C]verapamil (left image) and an iv microdose preceded by an oral therapeutic dose (1 mg/kg) of verapamil given 1 h before radiotracer injection (middle image). The right image shows the subject’s brain magnet resonance image (MRI). The radiation scale is set from 0 to 2.8 standardized uptake value (SUV). PET images were recorded on an Advance PET scanner (General Electrics Medical Systems). (B) Time-activity curves (mean SUV±SD) of (R)-[11C]verapamil in whole brain grey matter after administration of an iv microdose (open squares) and an iv microdose preceded by an oral therapeutic dose (1 mg/kg) of racemic verapamil given 1 h before radiotracer injection (filled diamonds) in 6 healthy volunteers. The chemical structure of (R)-[11C]verapamil is shown on top of the graph.
Figure 4
Figure 4
Plasma concentration-time curves (mean SUV±SD) of a radiolabeled iv microdose (1 mg) of [18F]ciprofloxacin given as a bolus over 20 sec to 4 patients with lower extremity soft tissue infection (open squares) and of an iv microdose of [18F]ciprofloxacin preceded by an oral therapeutic dose of ciprofloxacin (250 mg), given 3 h before the iv dose to 12 healthy subjects (filled diamonds). The chemical structure of [18F]ciprofloxacin is shown on top of the graph.

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