PT  - JOURNAL ARTICLE
AU  - Andreas Bauer
AU  - Marcus H. Holschbach
AU  - Markus Cremer
AU  - Simone Weber
AU  - Christian Boy
AU  - N. Jon Shah
AU  - Ray A. Olsson
AU  - Horst Halling
AU  - Heinz H. Coenen
AU  - Karl Zilles
TI  - Evaluation of <sup>18</sup>F-CPFPX, a Novel Adenosine A<sub>1</sub> Receptor Ligand: In Vitro Autoradiography and High-Resolution Small Animal PET
DP  - 2003 Oct 01
TA  - Journal of Nuclear Medicine
PG  - 1682--1689
VI  - 44
IP  - 10
4099  - http://jnm.snmjournals.org/content/44/10/1682.short
4100  - http://jnm.snmjournals.org/content/44/10/1682.full
SO  - J Nucl Med2003 Oct 01; 44
AB  - Adenosine modulates brain activity through 4 G protein-coupled receptors, primarily adenosine A1 receptors (A1ARs). A1ARs are heterogeneously distributed throughout the brain and participate in many physiologic processes—for example, the induction of sleep and feedback inhibition of excitatory neurotransmission. There is also evidence that A1ARs are involved in brain pathologies, including cerebral ischemia, epilepsy, and neurodegeneration. Therefore, measuring A1ARs in the living brain has been a long-standing goal. This report describes the preclinical evaluation of 18F-8-cyclopentyl-3-(3-fluoropropyl)-1-propylxanthine (18F-CPFPX), a novel A1AR PET ligand. Methods: CPFPX, a xanthine-based A1AR antagonist, was labeled with either 18F or 3H, maintaining identical chemical structures, and evaluated in rats as a putative radioligand for in vivo or in vitro imaging of brain A1ARs by quantitative receptor autoradiography and the combination of high-resolution small animal PET and MRI. Results: 3H-CPFPX bound with nanomolar affinity (Kd, 4.4 nmol/L) to A1ARs and showed a distribution typical of cerebral A1ARs. In extensive in vitro competition studies, 3H-CPFPX proved to be a highly selective and specific A1AR radioligand. Neither the nonxanthine-type adenosine A2A receptor antagonist ZM 241385 nor multiple cholinergic, serotoninergic, and glutamatergic receptor compounds competed for 3H-CPFPX below the micromolar level. In vivo animal PET and ex vivo autoradiographic experiments measured radioactivity in discrete brain regions after intravenous injection of 18F-CPFPX. 18F-CPFPX had excellent in vivo stability and penetrated the blood-brain barrier immediately after injection due to its high lipophilicity. Brain uptake was rapid and particularly high in gray matter regions. Retention of 18F-CPFPX was highest in the cerebellum, thalamus, and neocortex with evidence of saturable binding. Low binding potentials were found in the midbrain. In vivo displacement PET experiments with the A1AR antagonist 8-cyclopentyl-1,3-dipropylxanthine showed a 72% ± 8% displacement of 18F-CPFPX. Conclusion: 18F-CPFPX is a highly selective and specific ligand for A1ARs and a suitable radioligand for noninvasive PET imaging of A1ARs in the living brain. These studies also support the application of high-resolution animal PET as an effective in vivo imaging tool in the evaluation process of new radioligands.