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Novel 18 F-Labeled α-Methyl-Phenylalanine Derivative with High Tumor Accumulation and Ideal Pharmacokinetics for Tumor-Specific Imaging.
- Source :
-
Molecular pharmaceutics [Mol Pharm] 2019 Aug 05; Vol. 16 (8), pp. 3609-3616. Date of Electronic Publication: 2019 Jul 10. - Publication Year :
- 2019
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Abstract
- Positron emission tomography (PET) imaging with <superscript>18</superscript> F-labeled α-methyl-substituted amino acids exerts significant influence on differential diagnosis of malignant tumors and tumor-like lesions. Exclusive uptake via L-type amino acid transporter 1 (LAT1), a tumor-specific transporter, accounts for their excellent tumor specificity and low background accumulation. However, further refinement and optimization in their tumor accumulation and pharmacokinetics are sorely needed. To address these issues, we newly designed <superscript>18</superscript> F-labeled α-methyl-phenylalanine ( <superscript>18</superscript> F-FAMP) regioisomers (2-, 3-, or 4- <superscript>18</superscript> F-FAMP) and stereoisomers (L- or D-form), and we comprehensively evaluated their potential as tumor-imaging agents. <superscript>18</superscript> F-FAMPs were prepared from α-methyl phenylalanine by electrophilic radiofluorination and purified by reversed-phase HPLC. In biodistribution studies on normal mice, L-2- <superscript>18</superscript> F-FAMP and the three D- <superscript>18</superscript> F-FAMPs showed faster blood clearance and lower renal accumulation than L-3- <superscript>18</superscript> F-FAMP or L-4- <superscript>18</superscript> F-FAMP. In LS180 human colorectal cancer cell line xenograft mice, L-2- <superscript>18</superscript> F-FAMP exhibited significantly higher tumor accumulation than the D- <superscript>18</superscript> F-FAMPs or a clinically relevant tracer, L-3- <superscript>18</superscript> F-α-methyl-tyrosine ( <superscript>18</superscript> F-FAMT) ( p < 0.05). The renal accumulation levels of L-2- <superscript>18</superscript> F-FAMP were significantly lower than that of <superscript>18</superscript> F-FAMT ( p < 0.01). LAT-1 specificity of L-2- <superscript>18</superscript> F-FAMP was validated in the cellular uptake studies. The PET imaging with L-2- <superscript>18</superscript> F-FAMP clearly visualized the tumor as early as 1 h after injection, and the high tumor accumulation level was retained for 3 h. These findings suggest that L-2- <superscript>18</superscript> F-FAMP constitutes a potential PET tracer for tumor-specific imaging.
- Subjects :
- Animals
Cell Line, Tumor
Diagnosis, Differential
Humans
Injections, Intravenous
Large Neutral Amino Acid-Transporter 1 metabolism
Male
Mice
Neoplasms pathology
Phenylalanine administration & dosage
Phenylalanine chemistry
Phenylalanine pharmacokinetics
Positron-Emission Tomography methods
Radiopharmaceuticals administration & dosage
Radiopharmaceuticals chemistry
Tissue Distribution
Xenograft Model Antitumor Assays
Fluorine Radioisotopes
Neoplasms diagnostic imaging
Phenylalanine analogs & derivatives
Radiopharmaceuticals pharmacokinetics
Subjects
Details
- Language :
- English
- ISSN :
- 1543-8392
- Volume :
- 16
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Molecular pharmaceutics
- Publication Type :
- Academic Journal
- Accession number :
- 31242385
- Full Text :
- https://doi.org/10.1021/acs.molpharmaceut.9b00446