Purpose

CXCR4 is one of several “chemokine” receptors expressed on malignant tumors (including GBM and PCNSL) and hematopoietic stem cells. Although ⁶⁸Ga-pentixafor and ⁶⁸Ga-NOTA-NFB have been shown to effectively image CXCR4 expression in myeloma and other systemic malignancies, imaging CXCR4 expression in brain tumors has been more limited due to the blood-brain barrier (BBB) and a considerable fraction of CXCR4 staining is intracellular.

Methods

We synthesized 6 iodinated and brominated cyclam derivatives with high affinity (low nM range) for CXCR4, since structure-based estimates of lipophilicity suggested rapid transfer across the BBB and tumor cell membranes.

Results

We tested 3 iodinated and 3 brominated cyclam derivatives in several CXCR4(+) and CXCR4(−) cell lines, with and without cold ligand blocking. To validate these novel radiolabeled cyclam derivatives for diagnostic CXCR4 imaging efficacy in brain tumors, we established appropriated murine models of intracranial GBM and PCNSL. Based on initial studies, ¹³¹I-HZ262 and ⁷⁶Br-HZ270-1 were shown to be the most avidly accumulated radioligands. ⁷⁶Br-HZ270-1 was selected for further study in the U87-CXCR4 and PCNSL #15 intracranial tumor models, because of its high uptake (9.5 ± 1.3 %ID/g, SD) and low non-specific uptake (1.6 ± 0.7 %ID/g, SD) in the s.c. U87-CXCR4 tumor models. However, imaging CXCR4 expression in intracranial U87-CXCR4 and PCNSL #15 tumors with ⁷⁶Br-HZ270-1 was unsuccessful, following either i.v. or spinal-CSF injection.

Conclusions

Imaging CXCR4 expression with halogenated cyclam derivatives was successful in s.c. located tumors, but not in CNS located tumors. This was largely due to the following: (i) the hydrophilicity of the radiolabeled analogues—as reflected in the “measured” radiotracer distribution (LogD) in octanol/PBS—which stands in contrast to the structure-based estimate of LogP, which was the rationale for initiating the study and (ii) the presence of a modest BTB in intracranial U87-CXCR4 gliomas and an intact BBB/BTB in the intracranial PCNSL animal model.

中文翻译：

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使用碘化和溴化仙客来衍生物对 CXCR4 表达进行成像。

 目的

CXCR4是在恶性肿瘤（包括GBM和PCNSL）和造血干细胞上表达的几种“趋化因子”受体之一。尽管⁶⁸ Ga-pentixafor 和⁶⁸ Ga-NOTA-NFB 已被证明可以有效地对骨髓瘤和其他系统性恶性肿瘤中的 CXCR4 表达进行成像，但由于血脑屏障 (BBB) 和相当大的影响，脑肿瘤中 CXCR4 表达的成像受到更多限制。 CXCR4 染色的一部分是细胞内的。

 方法

我们合成了 6 种对 CXCR4 具有高亲和力（低 nM 范围）的碘化和溴化仙客来衍生物，因为基于结构的亲脂性估计表明可以快速转移穿过 BBB 和肿瘤细胞膜。

 结果

我们在几种 CXCR4(+) 和 CXCR4(−) 细胞系中测试了 3 种碘化和 3 种溴化仙客来衍生物，有或没有冷配体阻断。为了验证这些新型放射性标记仙客来衍生物在脑肿瘤中的 CXCR4 成像诊断功效，我们建立了适当的颅内 GBM 和 PCNSL 小鼠模型。根据初步研究， ¹³¹ I-HZ262 和⁷⁶ Br-HZ270-1 被证明是最容易积累的放射性配体。选择⁷⁶ Br-HZ270-1 在 U87-CXCR4 和 PCNSL #15 颅内肿瘤模型中进行进一步研究，因为其高摄取 (9.5 ± 1.3 %ID/g, SD) 和低非特异性摄取 (1.6 ± 0.7 sc U87-CXCR4 肿瘤模型中的％ID/g，SD）。然而，在静脉注射或脊髓脑脊液注射后，用⁷⁶ Br-HZ270-1 对颅内 U87-CXCR4 和 PCNSL #15 肿瘤中的 CXCR4 表达进行成像并不成功。

 结论

使用卤化仙客来衍生物对 CXCR4 表达进行成像在皮下肿瘤中是成功的，但在中枢神经系统肿瘤中则不然。这主要是由于以下原因：(i) 放射性标记类似物的亲水性——如辛醇/PBS 中“测量的”放射性示踪剂分布 (LogD) 所反映的——这与基于结构的 LogP 估计形成鲜明对比，后者是启动该研究的基本原理以及 (ii) 颅内 U87-CXCR4 神经胶质瘤中存在适度的 BTB 以及颅内 PCNSL 动物模型中存在完整的 BBB/BTB。