[18F]RPS-544: A PET tracer for imaging the chemokine receptor CXCR4.
Nucl Med Biol
; 60: 37-44, 2018 05.
Article
em En
| MEDLINE
| ID: mdl-29544122
ABSTRACT
INTRODUCTION:
CXCR4 specific [18F]-labeled positron emission tomography (PET) imaging agents are needed which would enable general distribution of the radiotracer for clinical investigation. We sought to synthesize, radiolabel and evaluate [18F]RPS-544, a novel non-peptide CXCR4 antagonist as a CXCR4 specific probe. We compared [18F]RPS-544 with the previously published [18F]-3 ([18F]RPS-510 in this paper) in a bi-lateral tumor model of differential CXCR4 expression for its ability to selectively target CXCR4 expression.METHODS:
Radiolabeling of [18F]RPS-544 and [18F]RPS-510 was performed by aromatic substitution on a 6-nitropyridyl group using no-carrier-added [18F]fluoride under basic conditions. 18F incorporation was determined by radioHPLC. Semi-preparative HPLC was used to purify the final product prior to reformulation. Imaging and biodistribution was performed in nude mice with bilateral PC3 (CXCR4+ and WT) xenograft tumors at 1, 2 and 4â¯h post injection.RESULTS:
RPS-544 bound CXCR4 with an IC50 of 4.9⯱â¯0.3â¯nM. [18F]RPS-544 showed preferential uptake in CXCR4+ tumors, with a CXCR4/WT ratio of 3.3⯱â¯1.3 at 1â¯h p.i. and 2.3⯱â¯0.5 at 2â¯h p.i. Maximum uptake in the CXCR4+ tumors was 3.4⯱â¯1.2%ID/g at 1â¯h p.i., significantly greater (pâ¯=â¯0.003) than the uptake in the WT tumor. Tumor/blood ratios were 2.5⯱â¯0.4 and 3.6⯱â¯0.3 at 1 and 2â¯h p.i. Tumor/muscle ratios were >4 at all time-points. Tumor/lung ratios were >2 at 1â¯h and 2â¯h p.i. Substantial uptake was observed in the liver (15-25%ID/g), kidneys (25-35%ID/g), the small intestine (1-7%ID/g) and the large intestine (1-12%ID/g). Blood concentrations varied over time (0.5-2%ID/g). All other organs showed uptake of <1%ID/g at all time points studied with clearance profiles similar to blood clearance.CONCLUSIONS:
Here we present, to the best of our knowledge, the first high affinity [18F]-labeled tracer, suitable for in vivo PET imaging of CXCR4. [18F]RPS-544 displayed high affinity for CXCR4 and good tumor uptake with a maximum uptake at 1â¯h p.i.. CXCR4 dependent uptake was demonstrated using bilateral tumors with differential CXCR4 expression as well as pharmacological blockade using the known CXCR4 antagonist, AMD-3100. Tissue contrast as judged by tumor to normal tissue ratios was positive in several key tissues. The structural and pharmacological similarities between [18F]RPS-544 and the approved drug AMD-3465, combined with the ease of synthesis and high molar activity (>185â¯GBq/µmol) achieved during radiosynthesis could lead to accelerated translation into the clinic.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Compostos Radiofarmacêuticos
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Receptores CXCR4
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Tomografia por Emissão de Pósitrons
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Nucl Med Biol
Assunto da revista:
BIOLOGIA
/
MEDICINA NUCLEAR
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Estados Unidos